|Ahead of print publication
A classification of genes involved in normal and delayed male puberty
Maleeha Akram1, Syed Shakeel Raza Rizvi1, Mazhar Qayyum1, David J Handelsman2
1 Department of Zoology, Wildlife and Fisheries, Pir Mehr Ali Shah Arid Agriculture University Rawalpindi, Shamsabad, Murree Road, Rawalpindi 46300, Pakistan
2 Andrology Laboratory, The ANZAC Research Institute, Hospital Road, Concord, NSW 2139, Australia
|Date of Submission||10-Sep-2021|
|Date of Acceptance||20-Feb-2022|
|Date of Web Publication||29-Apr-2022|
Department of Zoology, Wildlife and Fisheries, Pir Mehr Ali Shah Arid Agriculture University Rawalpindi, Shamsabad, Murree Road, Rawalpindi 46300
Source of Support: None, Conflict of Interest: None
Puberty is a pivotal biological process that completes sexual maturation to achieve full reproductive capability. It is a major transformational period of life, whose timing is strongly affected by genetic makeup of the individual, along with various internal and external factors. Although the exact mechanism for initiation of the cascade of molecular events that culminate in puberty is not yet known, the process of pubertal onset involves interaction of numerous complex signaling pathways of hypothalamo-pituitary-testicular (HPT) axis. We developed a classification of the mechanisms involved in male puberty that allowed placing many genes into physiological context. These include (i) hypothalamic development during embryogenesis, (ii) synaptogenesis where gonadotropin releasing hormone (GnRH) neurons form neuronal connections with suprahypothalamic neurons, (iii) maintenance of neuron homeostasis, (iv) regulation of synthesis and secretion of GnRH, (v) appropriate receptors/proteins on neurons governing GnRH production and release, (vi) signaling molecules activated by the receptors, (vii) the synthesis and release of GnRH, (viii) the production and release of gonadotropins, (ix) testicular development, (x) synthesis and release of steroid hormones from testes, and (xi)the action of steroid hormones in downstream effector tissues. Defects in components of this system during embryonic development, childhood/adolescence, or adulthood may disrupt/nullify puberty, leading to long-term male infertility and/or hypogonadism. This review provides a list of 598 genes involved in the development of HPT axis and classified according to this schema. Furthermore, this review identifies a subset of 75 genes for which genetic mutations are reported to delay or disrupt male puberty.
Keywords: delayed puberty; gonadotropin releasing hormone; hypogonadism; male puberty; puberty; testosterone
Article in PDF
| Introduction|| |
Puberty is a pivotal biological process that completes sexual maturation to achieve full reproductive capability. Occurring in early adolescence, it comprises appearance of changes in growth, behavior, and psychology of the individual becoming a reproductively competent adult. Puberty is a major transformational period of life with its timing strongly influenced by genetic makeup of the individual, with strong influence from various internal and external factors including environmental factors on the genetic background. A number of genes are turned on or off to develop a complicate series of physiological events fundamental for pubertal onset. Day et al. revealed the importance of biological genetic mechanisms on the timing and tempo of pubertal development. A recent study has shown that the genetic factors contribute about 50%–80% in determining the time for initiation of puberty. Some additional environmental factors are also fundamental in regulating the time of puberty, e.g., metabolic status of individuals such as malnutrition or obesity,, the presence of harmful chemicals in the environment known as endocrine disruptors (EDs), and physical conditions of individuals, e.g., hard-exercise or chronic disease (including malabsorption). These conditions may also delay the onset of puberty and subsequently impair reproductive function. Due to this strong interplay between timing of puberty and number of internal and external factors, extensive research has been conducted towards elucidating mechanisms involved in pubertal onset, modulatory factors that regulate the process of puberty, and how pubertal onset is affected in health and disease.
Although the ultimate trigger to initiate the cascade of molecular events that culminate in puberty is not yet known, the process of pubertal onset involves interaction of numerous complex signaling pathways of hypothalamo-pituitary-testicular (HPT) axis. These include (i) the development of the hypothalamus during embryonic development, (ii) the formation of neuronal connections between gonadotropin releasing hormone (GnRH) neurons and suprahypothalamic neurons during the process of synaptogenesis, (iii) maintenance of neuron homeostasis, (iv) the presence of molecules that regulate the synthesis and secretion of GnRH, (v) the presence of appropriate receptors/proteins on GnRH neurons for its production and release, (vi) the activation of proper signaling molecules by the receptors, (vii) the ability of GnRH neurons to coordinate and regulate GnRH synthesis and release, (viii) the ability of the pituitary gland to produce and release gonadotropins (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]), (ix) proper development of testes, (x) appropriate synthesis and release of steroid hormones from testes, and (xi) suitable action of steroid hormones in the downstream effector tissues. This review provides a list of 598 genes (excluding the duplicated genes), gathered from literature to identify important genes involved in the development of the HPT axis. Furthermore, 75 genes were identified among them in which genetic mutations have been reported to delay or disrupt male puberty.
| Hypothalamic Development|| |
During embryonic development after gastrulation phase, nervous system, including the hypothalamus, begins to form under the influence of various morphogens. At the initial stages, these morphogens are secreted from nonneural cells such as mesodermal domain, anterior prechordal plate, axial notochord, and other extra lateral tissues. Later on, these morphogens are produced from neural cells, which are close to the hypothalamic area. As the development progresses, sharp boundaries within the nervous system are formed, which are controlled by transcription factors that identify the final fate of neural cells and form different hypothalamic nuclei.,
The embryonic development of the hypothalamus starts from prechordal germ layer and involves four subsequent processes: (i) formation of regional territories and subdivisions of regional territories of the hypothalamus for the residence of GnRH neurons, (ii) differentiation of GnRH neurons, (iii) migration of neurons, and (iv) establishment of nuclei of the hypothalamus. It was suggested that an enormous number of transcripts are involved at different levels of the development of the hypothalamus.
Formation of regional territories and subdivisions of regional territories of the hypothalamus
The two most important signaling pathways fundamental for nervous system development are sonic hedgehog (Shh) and wingless family (Wnt) pathways. Shh and Wnt act as mitogens to control the production of neural tissues and maintain the transcription and translation rates of downstream genes. Shh and Wnt pathways are also required for the establishment of hypothalamic regional territories during embryogenesis.
The mechanism by which the ventricular zone (VZ) of the neuroepithelium is initiated to form the hypothalamus is complex. Experiments on zebrafish, chicken and mouse embryos have shown that the axial mesoderm plays a fundamental role in the development of hypothalamic regional territories through Shh signaling., It was observed that morphogens cause the movement of neural plate and axial mesoderm, which sequentially expose the hypothalamic floor plate. Afterward, Shh and Wnt signaling pathways interact with other signaling cascades such as fibroblast growth factors (FGFs), bone morphogenetic protein 7 (BMP7), and Nodal signaling to instruct the progenitor cells to form four hypothalamic regions: preoptic, anterior, tuberal, and mammillary. The previous work has also shown that during the formation of regional territories and subdivisions of regional territories of the hypothalamus, a number of transcription factors play their roles. The list of 53 genes that have an established role in the development of hypothalamic regional territories and subdivisions of regional territories,,,,,,, is shown in [Supplementary Table 1 [Additional file 1]], and mutations in 8 genes have previously been identified to cause delayed puberty,, [Table 1].
|Table 1: List of 75 genes in which mutations have been confirmed to cause delayed puberty|
Click here to view
GnRH neuron differentiation
GnRH neurons are a small population of more than 2000 neurons in humans. They are randomly distributed in preoptic area (POA) and arcuate nucleus (ARC) of the hypothalamus and form an “inverted Y-shape”. In humans and other primates, most of the GnRH neuron cell bodies are present more dorsally in the ARC but the exact number is not known. The morphology of GnRH neurons is also unique in that they have two “dendrons” extending from opposite sides of their cell bodies. Dendrons are processes that function both as dendrites and axons. Since GnRH neurons receive synaptic input and produce action potentials, they are also known as dendrons.,
In 1989, two separate research teams identified that GnRH neurons, which were presented in the hypothalamus in an adult, did not originate in this area of the brain., It was revealed that some GnRH neurons (approximately 30%) originate from neural crest cells and the remaining population (approximately 70%) originate from nasal/olfactory placode.,, Thus, the differentiation of GnRH neurons takes place at two levels – neural crest cells and nasal placode. A number of previous studies have demonstrated that certain growth factors are involved in neuronal differentiation., [Supplementary Table 2 [Additional file 2]] represents the list of 71 genes that have a role in GnRH neuronal differentiation,,, and mutations in 10 genes have been reported to be involved in delayed puberty,,, [Table 1].
GnRH neuron migration
After their differentiation, GnRH neurons from neural crest cells move to nasal placode, join the other population and then all neurons move to the hypothalamus along with vomeronasal axons.,, The migration process of GnRH neurons is represented in four processes. (i) After their origination in the olfactory placode, GnRH neurons migrate accompanied by vomeronasal axons toward the forebrain through the nasal mesenchyme., During this process, additional factors such as anosmin, ephrins, nasal embryonic LHRH factor (NELF), fibroblast growth factor 8/fibroblast growth factor receptor 1 (FGF8/FGFR1), and prokineticin and its receptor (PROK2/PROKR2) are required for keeping the GnRH and vomeronasal axons together during the movement. (ii) When both GnRH and vomeronasal axons reach the cribriform plate, vomeronasal axons divide and produce one branch that leads the GnRH neurons towards the forebrain. At this point, guidance molecules such as netrin 1/deleted in colorectal cancer (DCC), semaphorins/plexins and reelin guide the movement of GnRH neurons. (iii) During their movement from cribriform plate to the hypothalamus, GnRH neurons extend their branches toward median eminence (ME) under the influence of molecules such as hepatocyte growth factor (HGF), AXL/TYRO3 and stromal cell derived factor/CXC chemokine receptor (SDF1/CXCR4). (iv) In the last step, the GnRH neurons separate from their guides, distribute randomly in the hypothalamus and stop their movement.,
Along the migration from nose to the brain, a number of molecules guide the GnRH neurons in correct direction and also control the speed of migrating neurons. Gamma amino butyric acid (GABA) is known to decrease the speed of migrating neurons by causing depolarization but it helps the neurons to move in straight direction. Similarly, another molecule SDF increases the speed of neurons by triggering hyperpolarization of G-protein coupled inwardly rectifying potassium (GIRK) channels. Alternative guiding cues such as Semaphorins and HGFs also regulate movement of GnRH neurons. [Table 2] shows the list of 117 genes that have a role in the migration of GnRH neurons,,,,,,,, and mutations in 34 genes have been identified to cause delayed puberty,,,,,, [Table 1].
Development of hypothalamic nuclei
Although the hypothalamus is small, it consists of discrete nuclei that are scattered throughout the space it occupies and they secrete a number of neurotransmitters and peptide hormones. The development of hypothalamic nuclei begins by origination and migration of specific neurons. The previous work revealed that transcription factors such as NK2 homeobox 1 (NKX2.1), empty spiracles homeobox 2 (EMX2), distal-less homeobox 2 (DLX2), retinal homeobox protein 3 (RX3), and growth factors such as FGFs are important for hypothalamic nuclei development.,,, These transcription factors are directly or indirectly regulated by Shh and Wnt signaling pathways. [Supplementary Table 3 [Additional file 3]] represents the list of 25 genes that have a role in hypothalamic nuclei formation,, and mutations in 3 genes have been reported to be involved in delayed puberty [Table 1].
| Synaptogenesis|| |
Even though GnRH neurons reach the hypothalamus during embryonic development, they need to make contacts with other neurons, such as glutamatergic, GABAergic, kisspeptin-neurokinin B-dynorphin (KNDy) neurons. This process of making connections among neurons is known as synaptogenesis. GnRH neurons also make connections with nonneural cells called glia, which secrete different chemicals known as gliotransmitters, which control the activity of GnRH neurons. Studies have shown that each GnRH neuron is connected to about 5 000 000 other neurons, as second order connections., These suprahypothalamic neurons control the synthesis and secretion of GnRH to regulate the synthesis of gonadotropins from the pituitary.
The process of synaptogenesis is regulated by internal environment of GnRH neurons as well as many external factors. Certain growth factors such as Wnt, transforming growth factors (TGFs), tumor necrosis factors (TNFs), and ligand/receptor partners (such as semaphorins/plexins-neuropilins, Slit/Robo, Eph/ephrins, and netrins/Unc5-Dcc,), act as regulators of axon guidance for synaptogenesis. [Supplementary Table 4 [Additional file 4]] represents the list of 74 genes that have a role in synaptogenesis,,,,,, and mutations in 28 genes have previously been identified to cause delayed puberty,,,,,, [Table 1].
| Neuron Homeostasis|| |
Within the nervous system, most neurons are born during embryonic development and operate without replacement throughout the lifetime of the individual. Proteins are continuously made and degraded in neurons, and correct protein degenerative pathways are necessary for maintaining the homeostasis and efficient operations of neurons., In neurons, two mechanisms exist for maintaining the homeostasis. The first is autophagy, where lysosomes engulf and destroy the superfluous components of the neuron. The other is ubiquitination, where enzymes mark and degrade the misfolded or older proteins. Failure in these mechanisms results in axonal degeneration or neuronal death. [Supplementary Table 5 [Additional file 5]] represents the list of 25 genes that have a role to play in maintaining neuronal homeostasis in the HPT axis,,,,,, and mutations in 8 genes have been reported to be involved in delayed puberty,,, [Table 1].
| Molecules that Regulate GnRH Neuron Activity|| |
The onset of puberty is dependent on increase in the GnRH neuronal activity, which, in turn, increases the expression of GnRH1 gene, and secretes GnRH into hypophyseal portal blood in pulses. The exact mechanism triggering the onset of pulsatile GnRH secretion is still not well characterized. However, it has been proposed that the GnRH neuronal activity is controlled by upstream neuronal networks through neurotransmitters and neuromodulators. These upstream signals provide the information about body's status to GnRH neurons and determine whether puberty should be initiated or not. This complex network allows GnRH neurons, scattered in the hypothalamus, to synchronize and release GnRH in pulses.
A variety of neurotransmitters as well as neuromodulators plays roles in regulating the GnRH neuronal activity. Some are stimulatory such as kisspeptin, glutamate, leptin, neurokinin B, and insulin while others such as GABA, neuropeptide Y (NPY), opioids, ghrelin, cholecystokinin, and dopamine are inhibitory to GnRH neurons. The involvement of multiple innervations from suprahypothalamic areas may provide flexibility and precise coordination in the regulation of the GnRH neuronal activity manifested in the episodic release of GnRH. [Table 3] shows the list of 51 genes that have been identified to modulate GnRH neuronal activity,,,,,,, and mutations in 9 genes have been identified to cause delayed puberty,,, [Table 1].
|Table 3: List of 51 genes that code for molecules involved in regulating the GnRH neuron activity|
Click here to view
| Receptors/Proteins on GnRH Neurons|| |
GnRH neurons are responsive to a wide array of neurotransmitters and neuromodulators, which is reflected in the large number of receptors identified on adult GnRH neurons, as well as GnRH neurons in nasal explants.,, [Supplementary Table 6 [Additional file 6]] represents the list of 63 genes coding for receptors/proteins present on GnRH neurons that control the synthesis and secretion of GnRH,,,,,,, and mutations in 3 genes have been reported to be involved in delayed puberty, [Table 1].
| Signaling Molecules|| |
When the neurotransmitters or neuromodulators bind to their receptors on GnRH neurons, the activated receptors stimulate multiple signaling pathways. The signaling molecules act as on/off switches to transfer information from outer membrane to DNA inside the nucleus, where the information is further processed through DNA transcription and translation. Most of the receptors are G protein coupled receptors (GPCR), while some are receptor tyrosine kinases (RTKs).
GPCRs are heterotrimeric proteins, i.e., composed of α, β, and γ subunits and are able to bind different G proteins isoforms: Gs, Gi, Gq/11, and G12/13., When a ligand binds to GPCR, a conformational change occurs leading to the formation of guanosine triphosphate (GTP) from guanosine diphosphate (GDP). Gs isoform stimulates adenylate cyclase (AC), which stimulates cyclic adenosine monophosphate (cAMP) production, which, in turn, activates two processes; desensitizing GPCR together with activating cAMP response element (CREB), and mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK) pathway. In addition, Gq/11 isoform activates phospholipase C (PLC) pathways, which convert phosphatidyl inositol 4,5-bisphosphate (PIP2) to inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 and DAG sequentially increase the concentrations of intracellular Ca2+ ions, and regulate the nuclear factor kappa light chain enhancer of activated B cells (NF-κB). This, in turn, activates numerous protein kinase and signaling pathways, like protein kinase C (PKC)/MAPK/ERK., Furthermore, Gi isoform inhibits the AC. G12/13 isoform activates glycogen synthase kinase 3 (GSK3) in neurons,, which is involved in tau phosphorylation. GSK3, in turn, is inhibited by protein kinase B (Akt) and PKC. Moreover, by using β and γ subunits, GPCRs can activate phosphatidyl inositol 3-kinase (PI3K)/Akt cascades.,
In addition, when a ligand binds to RTKs, the receptor becomes phosphorylated and activates growth factor receptor bound protein 2 (GRB2) and Son of Sevenless (SOS), which further triggers Ras (small, monomeric GTP-binding proteins) and Ras activates serine/threonine kinase rapidly accelerated fibrosarcoma (Raf). Raf phosphorylates MAP/ERK kinase 1, 2 (Mek1/2), which sequentially phosphorylates and stimulates Erk1/2. Raf also activates MAP3 kinases that activate mitogen-activated protein kinase kinase 4, 7 (MKK4/7), mitogen-activated protein kinase kinase kinase 3, 6 (MKKK3/6 or MAP3Ks) and MEK5, which sequentially activates Jun N-terminal kinase 1, 2 (JNK1/2), p38, and ERK5. Furthermore, phosphorylation of RTKs also activates PI3K, which consecutively activates Akt and mammalian target of rapamycin (mTOR) within the mammalian target of rapamycin complex 1 (mTORC1) complex, which also regulates Akt. Moreover, PLC can also be activated by RTKs, leading to Ca2+ mobilization and activation of PKC.,,
Earlier research on embryonic mouse nasal explants has shown that all signaling pathways activated by GPCRs and RTKs are found in GnRH neural cells and the GnRH neuronal activity is controlled by downstream effectors of these receptors. It was identified that the TAM receptor family, which includes Tyro3, Axl and Mer, involved in GnRH neuron migration, activates several intracellular signaling pathways, including PI3K-Akt, ERK1/2, and/or p38 MAPK., Gas6/Axl stimulates the remodeling of cytoskeleton and causes the migration of GnRH neuronal cells through p38 PI3K and Rho family GTPase Rac signaling pathway. Axl phosphorylates the p85 subunit of PI3K and contributes to Rac activation, which is required for Gas6/Axl-induced neuron migration., Furthermore, semaphorin/neuropilin/plexin pathways that play different roles in the GnRH neuron biology by regulating migration and survival during embryonic development as well as secretion in adulthood use RTK signaling through FARP2, Rac1, Rnd1, PAK, LIMK1, and Cofilin pathways., Furthermore, kisspeptin/GPR54 system activates PLC pathway using Gq-dependent signaling pathway, and causes depolarization of GnRH neurons to regulate its secretion. Similarly, NPY inhibits the GnRH neuronal activity by utilizing Gi protein-coupled receptors, which inhibits AC and this represses signaling through the cAMP/PKA pathway., In addition, gliotransmitters secreted by glial cells control the synthesis and release of GnRH by using RTKs such as fibroblast growth factor receptor (FGFR), epidermal growth factor receptors (EGFRs), hepatocyte growth factor receptors (HGFRs), insulin and insulin-like growth factor receptors (IR and IGFR), vascular endothelial growth factor receptors (VEGFRs), and platelet-derived growth factor receptors (PDGFRs)., [Supplementary Table 7 [Additional file 7]] shows the list of 21 genes that have been identified to code for signaling molecules for GnRH production and secretion,,, and no mutations in signaling molecules have been identified to cause delayed puberty.
| Synthesis and Secretion of GnRH|| |
The hypothalamic POA and ARC house the soma of most of the GnRH neurons, but they extend their branches (>1 mm long) to ME, where they secrete GnRH into the hypophyseal portal blood system. Even though GnRH neurons are physically scattered in the hypothalamus, functionally they are highly coordinated.
At the time of pubertal onset, the expression of GnRH gene increases due to augmented influence from stimulatory neurotransmitters, which increase the synthesis of GnRH. The GNRH1 gene codes GnRH protein and consists of 3 exons and 3 introns. After translation, prepro-GnRH peptide is produced, which consists of 92 amino acids. Prepro-GnRH is comprised of N-terminal signal peptide, GnRH, cleavage signal and C-terminal GnRH associated peptide (GAP). Prepro-GnRH is converted into pro-GnRH peptide by removing the N-terminal signal peptide. Pro-GnRH is further cleaved by endopeptidases into GnRH peptide and GAP. Afterward, carboxypeptidase enzymes remove basic amino acids from C-terminus and glutaminyl cyclase enzymes convert the N-terminal glutamine to produce final bioactive GnRH peptide.,
The process of GnRH production is controlled at various steps such as transcription rate, posttranscriptional modifications, stability of mRNA, translation rate, and posttranslational modifications including conversion of inactive prepro-GnRH to biologically active GnRH decapeptide. Earlier studies have shown that transcription factors such as homeodomain protein orthodenticle homeobox 2 (OTX2) and the POU homeodomain protein transcription factor OCT1 are fundamental for GnRH gene transcription. Since then, numerous transcription factors have been identified to play a role in GnRH synthesis. Furthermore, a number of enzymes such as prohormone convertases (PCs), carboxypeptidases, glutaminyl cyclase, peptidylglycine α-amidating monooxygenase, and prolyl hydroxylase are also essential for full processing of GnRH molecule. [Table 4] represents the list of 104 genes that have a role to play in GnRH synthesis,,,,,,, and mutations in 7 genes have been reported to be involved in delayed puberty,,, [Table 1].
| Synthesis and Secretion of Gonadotropins|| |
At the time of pubertal onset, the pulsatility of GnRH increases as required for the augmentation of gonadotropins secretion and consequent final maturation of mature gonads. The pulsatility of GnRH is due to coordinated interaction between multiple GnRH neurons, which are controlled by stimulatory and inhibitory signals. The stimulatory signals increase the activity of voltage sensitive ion channels, causing an influx of Ca2+ ions. Broad changes in Ca2+ ions allow the GnRH vesicles to move toward the plasma membrane of GnRH neurons and by the process of exocytosis, secrete GnRH in the hypophyseal portal capillary bloodstream at the ME., In an adult male, GnRH neurons produce one pulse of GnRH every 2 h, which is required for continuous spermatogenesis leading to preparation of mature sperm capable of fertilizing oocytes when delivered to the site of fertilization in the female reproductive tract.
GnRH is secreted into the pituitary portal bloodstream to arrive at the pituitary gonadotrope cells, which are specialized for producing gonadotropins (LH and FSH). At the pituitary gonadotropes, GnRH binds with gonadotropin releasing hormone receptor (GnRHR) on the gonadotrope cell surface membrane. GnRHR is a GPCR that consists of seven transmembrane domains. The activation of GnRHR is dependent on the episodic secretion of the hypothalamic GnRH. When GnRH binds with GnRHR, Gq/11 isoform activates and stimulates the PLC signaling pathway. As a result, IP3 and DAG are produced. IP3 activates its receptor IP3R, causing an influx of Ca2+ ions to release gonadotropins from their vesicles into systemic circulation. On the other hand, DAG along with Ca2+, stimulates PKC, which activates Raf/MEK/ERK cascade. In addition, Ca2+ stimulates calmodulin (CaM) that triggers CaM-dependent protein kinases (CaMK) and the phosphatase calcineurin (Cn), which, in turn, activate Ca2+-dependent transcription factor nuclear factor of activated T-cells (NFAT). NFAT- and ERK-activated transcription factors work in synergy to regulate the synthesis of gonadotropins.
GnRH is secreted in pulses to drive pulses of gonadotropin release and is essential for normal reproduction. Its effects are dependent on pulse frequency. In humans and other primates, GnRH pulses have a duration of a few minutes and intervals of 30 min to several hours. When the levels of GnRH increase, GnRHR activates Gq/11 signaling pathway to increase the concentrations of Ca2+, which allows the fusion of vesicles with the plasma membrane thus, at high concentrations, GnRH causes the release of gonadotropins., Ca2+ also activates CaM pathway to activate the Ca2+-dependent transcription factor NFAT. In addition, GnRH stimulates MAPK pathway for the activation of the Raf/MEK/ERK cascade. NFAT- and ERK-activated transcription factors then act in combination to control gene expression of gonadotropins genes. Thus, chronically GnRH regulates the gonadotropin content of the vesicles. The stimulatory effects of GnRH on LH and FSH secretion are different. The secretion of FSH is more irregular than LH in humans, which is essentially related to the pulsatility and different stimulatory effects of GnRH. LH is synthesized when the frequency of GnRH pulses is high, while FSH is produced at lower frequency of GnRH pulses. Furthermore, there is a negative feedback effect of inhibin B on FSH secretion. Other factors are also involved, such as differences in LH and FSH storage (more scarce for the FSH), the existence of different gonadotrophic subpopulations, or diverse response times to GnRH., [Table 5] shows the list of 35 genes that have a role to play in gonadotropins synthesis and secretion,,,,,,, and mutations in 16 genes have previously been identified to cause delayed puberty,,,, [Table 1].
|Table 5: List of 35, 16, and 12 genes involved in the synthesis and secretion of gonadotropins, development of testes and steroidogenesis, respectively|
Click here to view
| Development of Testes|| |
The testicular development begins with the formation of the genital ridge. The primordial germ cells (PGCs) begin to colonize the gonads by approximately 5th week of gestation. By the 6th week, the PGCs invade the genital ridges., In genetically male embryos, testis determination occurs due to the presence of sex-determining region of the Y chromosome (SRY) gene, which stimulates the production of sex-determining proteins.,
The SRY gene encodes for a transcription factor that activates the testis-specific enhancer (TESCO) of a related autosomal gene known as SRY-box transcription factor 9 (SOX9). The SOX9 gene plays an important role in the differentiation of the Sertoli cells from supporting cell precursors. In addition to SRY, other factors such as steroidogenic factor 1 (encoded by the gene nuclear receptor subfamily 5 group A member 1 [NR5A1]), are also important for the differentiation of the Sertoli cells.,
SRY increases the concentrations of SOX9 and once the levels of SRY and SOX9 are high enough inside the cells/tissue, the transcription of SOX9 protein is maintained at higher levels in the Sertoli cells. As soon as the SOX9 positive cells reach sufficient levels in the gonads, morphological changes occur and the process of testes formation begins., This process involves the differentiation of interstitial cell lineages (Leydig cells and peritubular myoid cells), the mitotic arrest of germ cells, epithelialization of the Sertoli cells, and the formation of the testicular cords.,
The descent of testes from inside the abdomen to the scrotum is a continuous process that is divided into two main phases: the transabdominal phase and the inguinoscrotal phase. During the first transabdominal phase, the testes are attached with the inner entrance of the future inguinal canal, while in the second inguinoscrotal phase, the testes move through the inguinal canal and reach their final position, the scrotum. Studies on humans have shown that the transabdominal phase occurs between the gestational weeks 10 and 15 while the inguinoscrotal phase occurs between the 25th and 35th gestational weeks., [Table 5] shows the list of 16 genes involved in the development of testes,, and mutations in 5 genes have previously been reported to cause delayed puberty,,, [Table 1].
| Steroidogenesis|| |
LH and FSH are secreted in the systemic circulation, which takes them to testes, where receptors for both hormones are present on the target cell surface membranes. LH receptors (LHR or LHCGR) are present on the Leydig cells while the testicular Sertoli cells house FSH receptors (FSHR). When LH binds with LHR, there is a conformational change in LHR, which activates Gs isoform and stimulates AC, PLC/IP3, and ERK1/2/AKT signaling pathways. All these pathways work together to control the process of steroidogenesis in males.,
In the Leydig cells, steroidogenesis takes place to produce testosterone (T). Testes are responsible for production of >95% of the circulating T. On the other hand, adrenal glands are also involved in the production of minor quantity of T., Like other steroid hormones, T is synthesized from cholesterol. When LH binds with LHR, signaling cascade starts, which activates steroidogenic acute regulatory protein (StAR) to transfer cholesterol molecules into mitochondria. In the mitochondria, cholesterol is converted to pregnenolone through cytochrome P450 family 11 subfamily A member 1 (CYP11A1 or P450scc) and its redox partners, ferredoxin (FDX1) and ferredoxin reductase (FDXR). Pregnenolone is further converted to 17α-hydroxypregnenolone (17OHPreg) and dehydroepiandrosterone (DHEA) by using delta 5 pathway and CYP17A1 (P450c17) enzyme. DHEA is then converted to either androstenedione by using 3β-hydroxysteroid dehydrogenase type II (HSD3B2/3βHSDII) or to androstenediol through 17β-hydroxysteroid dehydrogenase 3 (HSD17B3/17βHSD3/AKR1C3)., Most of the T is converted to dihydrotestosterone (DHT) by steroid 5α-reductase, alpha polypeptide 1 (SRD5A1)., [Table 5] shows the list of 12 genes that are involved in the process of steroidogenesis,,, and mutations in only 1 gene have been reported to be involved in delayed puberty [Table 1].
| Steroid Hormone Action|| |
The action of androgens, notably T, occurs through androgen receptors (ARs; NR3C4), which are a family of nuclear, ligand-activated transcription factor receptors., In the absence of androgens, ARs are bound to heat shock proteins (HSPs) and co-repressors and are located in the cytoplasm in a latent state, devoid of any biological activity. When androgens bind with ARs, conformational changes occur, ARs become separated from HSPs and co-repressors and are transported to the nucleus by co-regulators. Inside the nucleus, ARs bind to specific androgen response elements leading to stimulation of various transcription factors to control the expression of downstream genes (canonical signaling). In addition, ARs can also activate Ca2+, IP3 and DAG signaling pathways for its nonclassical effects., Moreover, when androgens are present in small amounts, nongenomic signaling of ARs occurs through MAPK/Akt pathways. This nongenomic signaling regulates the propagation and survival of cells. [Supplementary Table 8 [Additional file 8]] represents the list of 115 genes that have a role to play in the action of steroid hormones,, and mutations in 5 genes have been identified to cause delayed puberty,,,, [Table 1].
| Molecular Basis of Delayed Puberty|| |
Male puberty requires an intact operational HPT axis and any interruption in this axis may result in temporary or permanent dysfunction of reproductive axis manifested as delayed or failed puberty. A mature, functional HPT axis of a reproductively competent adult requires properly regulated and coordinated development of the hypothalamus, pituitary, and testes during embryogenesis [Figure 1]. After embryonic development, GnRH neurons need to coordinate and regulate GnRH synthesis and release, which is required to stimulate the pituitary glands for the production and release of gonadotropins. In turn, gonadotropins must be capable of stimulating the testes for steroidogenesis (to produce androgens) and spermatogenesis (to produce mature sperm capable of fertilization). The steroids produced must also be able to perform their function correctly in the downstream effector tissues. Any abnormality in the development of the entire system either during embryonic development, childhood, adolescence or adulthood may disrupt or nullify puberty, leading to long-term male infertility and/or hypogonadism.
|Figure 1: A complex regulation of HPT axis. HPT: hypothalamo-pituitary-testicular; NKB: neurokinin B; GALP: galanine-like peptide; GABA: gamma amino butyric acid; DA: dopamine; NPY: neuropeptide Y; ENK: enkephalins; T: testosterone; DHT: dihydrotestosterone; GnRH: gonadotropin releasing hormone; LH: luteinizing hormone; FSH: follicle stimulating hormone.|
Click here to view
Male puberty is said to be delayed if it does not commence with increase in testis growth as the first external sign by the age of 14 years leading to persistence of immature small testes, which lack mature testis functions evident with impaired spermatogenesis in small testes of typically <4 ml of volume, reduced or absent sperm production (azoospermia or oligo-zoospermia) and deficient virilization due to impaired T secretion.,
Failure of the hypothalamus to develop properly, failure of GnRH neurons to differentiate, inability of GnRH neurons to reach the proper place in the hypothalamus and form appropriate connections, failure of GnRH neurons to coordinate with each other in producing GnRH, inability of GnRH to activate the pituitary gland, failure to stimulate steroidogenesis through gonadotropins or failure to activate ARs by steroids means that puberty is not initiated. The origin of most or all of these conditions is primarily genetic.
Although extensive research has been carried out on regulation of the male puberty, only 75 out of 598 genes have been identified to be mutated leading to delayed puberty. [Table 1] represents the list of genes along with the references in which mutations have been confirmed to cause delayed puberty. The genetic basis of delay in puberty remains unknown among 50% of the cases,, presumably those in the group of 598 genes not included among the 75 so far known genes associated with disruption of the male puberty or possibly still others. These unidentified cases will be increasingly revealed by using advanced genomics methods like next-generation sequencing (NGS) technologies, where massively parallel sequencing approaches produce millions of short-read sequences in a much shorter time, at a much cheaper cost and with higher throughput compared to Sanger sequencing. Two methods, whole genome sequencing (WGS; the method to determine the order of all the nucleotides in an individual's DNA) and whole exome sequencing (WES; the method of sequencing all the exons) are increasingly used in healthcare and research to identify genetic variations. These approaches are known as NGS. By using NGS, it is expected that more accurate and much less costly outcomes can be obtained to make them routine diagnostic tests making the transition from expensive research tests. It was observed that same mutation in different patients showed different phenotypes, even in monozygotic twins. This proposed the concept of digenicity or oligogenicity, where mutations in two or more genes enhance the effect of each other and produce variable phenotypes, as well as compound heterozygosity, where two different mutated alleles are present at a particular gene locus., It was also suggested that heterozygous mutations in different genes along the HPT axis synergize the effect of each other in producing the phenotype, but the contribution of each gene may be different in each patient and also, if these variants are present alone in heterozygous state then they may not contribute to the disease. In view of these observations, it was suggested that mutations in any of the genes involved in the development and functioning of the HPT axis may cause delayed puberty, Kallmann syndrome, or idiopathic hypogonadotropic hypogonadism.
There are a number of genes, which are involved in multiple processes along normal functioning HPT axis. Explaining the exact mechanism for each gene is beyond the scope of this article. For example, PIN1 is a peptidyl-prolyl cis-trans isomerase that catalyses the isomerization of phosphorylated Ser/Thr-Pro peptide bonds. It was observed in PIN1 knock-out mice that their reproductive development and function were markedly abnormal causing hypogonadotropic hypogonadism., The main role of PIN1 is in the transcription of gonadotropin-subunit genes. It promotes the ubiquitination of SF1 by using a phosphorylation-regulated pathway, which, in turn, allows the SF1 to interact with paired like homeodomain 1 (Pitx1) and increase the transcriptional activity of SF1. SF1 is involved in the regulation of transcription of several enzymes having a role in steroid/androgen biosynthesis. In the pituitary gonadotropes, GnRH-induced signaling cascades maintain the higher levels of activated PIN1 through transcriptional and posttranslational regulation. This indicates that PIN1 is involved in the GnRH signaling pathway and gonadotropin gene expression. PIN1 modulates the activity of various transcription factors for initiating the transcription of the gonadotropin β-subunit. PIN1 was also identified at the promoters of both gonadotropin β-subunit genes and it was predicted that this recruitment was due to its interaction with SF1, Pitx1, and/or early growth response 1 (Egr-1).,, In addition to its role in the synthesis of gonadotropins, PIN1 is also involved in the differentiation of neural progenitor cells by interacting with β-catenin and providing a postphosphorylation signaling mechanism for the regulation of developmental stage-specific functioning of β-catenin signaling in neuronal differentiation.
| Conclusions|| |
This review provides a classification of mechanisms controlled by a large number of genes, whose normal function leads to the proper development and function of the HPT axis and progression of normal male puberty. The disruption of the HPT axis due to mutations in some of the genes identified so far delays or disrupts male puberty. The present study is an interim synopsis of the genes involved in normal and disrupted male puberty and future studies are likely to still add more genes to already identified ones.
| Author Contributions|| |
MA and SSRR conceived and designed the work. MA performed data collection. SSRR, MQ and DJH supervised the work and helped in the critical revision of this article. All authors read and approved the final manuscript.
| Competing Interests|| |
All authors declare no competing financial interests.
| Acknowledgments|| |
The authors are very grateful to the ANZAC Research Institute, NSW, Australia, for accommodating and helping the researcher (Maleeha Akram) during her stay in Australia.
Supplementary Information is linked to the online version of the paper on the Asian Journal of Andrology website.
| References|| |
Plant TM. Neuroendocrine control of the onset of puberty. Front Neuroendocrin
2015; 38: 73–88.
Avendano MS, Vazquez MJ, Tena-Sempere M. Disentangling puberty: novel neuroendocrine pathways and mechanisms for the control of mammalian puberty. Hum Reprod Update
2017; 23: 737–63.
Terasawa E, Kurian JR. Neuroendocrine mechanism of puberty. In: Fink G, Pfaff DW, Levine JE, editors. Handbook of Neuroendocrinology. Cambridge: Academic Press; 2012. p433–84.
Day FR, Perry JR, Ong KK. Genetic regulation of puberty timing in humans. Neuroendocrinology
2015; 102: 247–55.
Lardone MC, Alexander S, Busch AS, Santos JL, Miranda P, et al.
A polygenic risk score suggests shared genetic architecture of voice break with early markers of pubertal onset in boys. J Clin Endocrinol Metab
2020; 105: dgaa003.
Castellano JM, Tena-Sempere M. Animal modeling of early programming and disruption of pubertal maturation. Endocr Dev
2016; 29: 87–121.
Castellano JM, Tena-Sempere M. Metabolic control of female puberty: potential therapeutic targets. Expert Opin Ther Targets
2016; 20: 1181–93.
Zawatski W, Lee MM. Male pubertal development: are endocrine-disrupting compounds shifting the norms? J Endocrinol
2013; 218: R1–12.
Parent AS, Franssen D, Fudvoye J, Pinson A, Bourguignon JP. Current changes in pubertal timing: revised vision in relation with environmental factors including endocrine disruptors. Endocr Dev
2016; 29: 174–84.
Quaynor SD, Bosley ME, Duckworth CG, Porter KR, Kim SH, et al.
Targeted next generation sequencing approach identifies eighteen new candidate genes in normosmic hypogonadotropic hypogonadism and Kallmann syndrome. Mol Cell Endocrinol
2016; 437: 86–96.
Hoch RV, Rubenstein JL, Pleasure S. Genes and signalling events that establish regional patterning of the mammalian forebrain. Semin Cell Dev Biol
2009; 20: 378–86.
Bedont JL, Newman EA, Blackshaw S. Patterning, specification, and differentiation in the developing hypothalamus. Wiley Interdiscip Rev Dev Biol
2015; 4: 445–68.
Gao Y, Sun T. Molecular regulation of hypothalamic development and physiological functions. Mol Neurobiol
2016; 53: 4275–85.
Szabo NE, Zhao T, Cankaya M, Theil T, Zhou X, et al
. Role of neuroepithelial sonic hedgehog in hypothalamic patterning. J Neurosci
2009; 29: 6989–7002.
Alvarez-Bolado G. Development of neuroendocrine neurons in the mammalian hypothalamus. Cell Tissue Res
2018; 375: 23–39.
Manning L, Ohyama K, Saeger B, Hatano O, Wilson SA, et al
. Regional morphogenesis in the hypothalamus: a BMP-Tbx2 pathway coordinates fate and proliferation through Shh downregulation. Dev Cell
2006; 11: 873–85.
Haddad-Tovolli R, Paul FA, Zhang Y, Zhou X, Theil T, et al
. Differential requirements for Gli2 and Gli3 in the regional specification of the mouse hypothalamus. Front Neuroanat
2015; 9: 34.
Lee JE, Wu SF, Goering LM, Dorsky RI. Canonical Wnt signalling through Lef1 is required for hypothalamic neurogenesis. Development
2006; 133: 4451–61.
Jeong Y, Leskow FC, El-Jaick K, Roessler E, Muenke M, et al
. Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein. Nat Genet
2008; 40: 1348–53.
Danesin C, Peres JN, Johansson M, Snowden V, Cording A, et al
. Integration of telencephalic Wnt and hedgehog signalling center activities by Foxg1. Dev Cell
2009; 16: 576–87.
Shimogori T, Lee DA, Miranda-Angulo A, Yang Y, Wang H, et al
. A genomic atlas of mouse hypothalamic development. Nat Neurosci
2010; 13: 767–75.
Vacik T, Stubbs JL, Lemke G. A novel mechanism for the transcriptional regulation of Wnt signalling in development. Genes Dev
2011; 25: 1783–95.
Hou H, Uuskula-Reimand L, Makarem M, Corre C, Saleh S, et al
. Gene expression profiling of puberty-associated genes reveals abundant tissue and sex-specific changes across postnatal development. Hum Mol Genet
2017; 26: 3585–99.
Cangiano B, Swee DS, Quinton R, Bonomi M. Genetics of congenital hypogonadotropic hypogonadism: peculiarities and phenotype of an oligogenic disease. Hum Genet
2021; 140: 77–111.
Howard SR, Dunkel L. Genetics of delayed puberty. In: Kohn B, editor. Pituitary Disorders of Childhood: Diagnosis and Clinical Management. London: Springer Nature; 2019. p251–68.
Kim JH, Seo GH, Kim GH, Huh J, Hwang IT, et al
. Targeted gene panel sequencing for molecular diagnosis of Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Exp Clin Endocrinol Diabetes
2019; 127: 538–44.
Rigobello C, Maggi R. Cell-based models to study GnRH neuron physiology. MOJ Anat Physiol
2017; 3: 1–6.
Constantin S. Physiology of the GnRH neuron: studies from embryonic GnRH neurons. J Neuroendocrinol
2011; 23: 542–53.
Smedlund KB, Hill JW. The role of non-neural cells in hypogonadotropic hypogonadism. Mol Cell Endocrinol
2020; 518: 110996.
Herde MK, Iremonger KJ, Constantin S, Herbison AE. GnRH neurons elaborate a long-range projection with shared axonal and dendritic functions. J Neurosci
2013; 33: 12689–97.
Schwanzel-Fukuda M, Pfaff DW. Origin of luteinizing hormone releasing hormone neurons. Nature
1989; 338: 161–4.
Wray S, Grant P, Gainer H. Evidence that cells expressing luteinizing hormone-releasing hormone mRNA in the mouse are derived from progenitor cells in the olfactory placode. Proc Natl Acad Sci U S A
1989; 86: 8132–6.
Suzuki J, Osumi N. Neural crest and placode contributions to olfactory development. Curr Top Dev Biol
2015; 111: 351–74.
Yoshida K, Tobet SA, Crandall JE, Jimenez TP, Schwarting GA. The migration of luteinizing hormone-releasing hormone neurons in the developing rat is associated with a transient, caudal projection of the vomeronasal nerve. J Neurosci
1995; 15: 7769–77.
Lemmon MA, Schlessinger J. Cell signalling by receptor tyrosine kinases. Cell
2010; 141: 1117–34.
Regad T. Targeting RTK signalling pathways in cancer. Cancers
2015; 7: 1758–84.
Xu C, Pitteloud N. Congenital hypogonadotropic hypogonadism (Isolated GnRH deficiency). In: Kohn B, editor. Pituitary Disorders of Childhood, Contemporary Endocrinology. London: Springer Nature; 2019. p229–50.
Hollis B, Day FR, Busch AS, Thompson DJ, Soares AL, et al
. Genomic analysis of male puberty timing highlights shared genetic basis with hair colour and lifespan. Nat Commun
2020; 11: 1536.
Forni PE, Wray S. Neural crest and olfactory system: new prospective. Mol Neurobiol
2012; 46: 349–60.
Shan Y, Wray S. Prenatal development of GnRH neurons. In: Herbison AE, Plant TM, editors. GnRH Neuron and Its Control. Chichester: Wiley Blackwell; 2018. p15–42.
Wierman ME, Kiseljak-Vassiliades K, Tobet S. Gonadotropin-releasing hormone (GnRH) neuron migration: initiation, maintenance and cessation as critical steps to ensure normal reproductive function. Front Neuroendocrinol
2011; 32: 43–52.
Herbison AE. Control of puberty onset and fertility by gonadotropin-releasing hormone neurons. Nat Rev Endocrinol
2016; 12: 452–66.
Casoni F, Hutchins BI, Donohue D, Fornaro M, Condie BG, et al
. SDF and GABA interact to regulate axophilic migration of GnRH neurons. J Neurosci
2012; 125: 5015–25.
Giacobini P, Messina A, Morello F, Ferraris N, Corso S, et al
. Semaphorin 4D regulates gonadotropin hormone–releasing hormone-1 neuronal migration through PlexinB1–Met complex. J Cell Biol
2008; 183: 555–66.
Giacobini P, Messina A, Wray S, Giampietro C, Crepaldi T, et al
. Hepatocyte growth factor acts as a mitogen and guidance signal for gonadotropin hormone-releasing hormone-1 neuronal migration. J Neurosci
2007; 27: 431–45.
Boehm U, Bouloux PM, Dattani MT, de Roux N, Dode C, et al
. Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism-pathogenesis, diagnosis and treatment. Nat Rev Endocrinol
2015; 11: 547–64.
Forni PE, Wray S. GnRH, anosmia and hypogonadotropic hypogonadism: where are we? Front Neuroendocrinol
2015; 36: 165–77.
Kim SH. Congenital hypogonadotropic hypogonadism and Kallmann syndrome: past, present, and future. Endocrinol Metab
2015; 30: 456–66.
Maione L, Dwyer AA, Francou B, Guiochon-Mantel A, Binart N, et al
. Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next generation sequencing. Eur J Endocrinol
2018; 178: 55–80.
Bouilly J, Messina A, Papadakis G, Cassatella D, Xu C, et al
. DCC/NTN1 complex mutations in patients with congenital hypogonadotropic hypogonadism impair GnRH neuron development. Hum Mol Genet
2018; 27: 359–72.
Xie T, Dorsky RI. Development of the hypothalamus: conservation, modification and innovation. Development
2017; 144: 1588–99.
Davis AM, Seney ML, Stallings NR, Zhao LP, Parker KL, et al
. Loss of steroidogenic factor 1 alters cellular topography in the mouse ventromedial nucleus of the hypothalamus. J Neurobiol
2004; 60: 424–36.
Pearson CA, Placzek M. Development of the medial hypothalamus: forming a functional hypothalamic-neurohypophyseal interface. Curr Top Dev Biol
2013; 106: 49–88.
Terasawa E. Postnatal development of GnRH neuronal function. In: Herbison AE, Plant TM, editors. GnRH Neuron and Its Control. Chichester: Wiley Blackwell; 2018. p61–91.
Herbison AE. Physiology of the adult gonadotropin-releasing hormone neuronal network. In: Plant TM, Zeleznik AJ, editors. Knobil and Neill's Physiology of Reproduction. Cambridge: Academic Press; 2015. p399–467.
Poon VY, Choi S, Park M. Growth factors in synaptic function. Front Synaptic Neurosci
2013; 5: 1–18.
Dickson BJ. Molecular mechanisms of axon guidance. Science
2002; 298: 1959–64.
Qu Y, Huang Y, Feng J, Alvarez-Bolado G, Grove EA, et al
. Genetic evidence that Celsr3 and Celsr2, together with Fzd3, regulate forebrain wiring in a Vangl-independent manner. Proc Natl Acad Sci U S A
2014; 111: 2996–3004.
Kulkarni A, Chen J, Maday S. Neuronal autophagy and intercellular regulation of homeostasis in the brain. Curr Opin Neurobiol
2018; 51: 29–36.
Spalding KL, Bhardwaj RD, Buchholz BA, Druid H, Frisen J. Retrospective birth dating of cells in humans. Cell
2005; 122: 133–43.
Maday S. Mechanisms of neuronal homeostasis: autophagy in the axon. Brain Res
2016; 1649: 143–50.
Groen EJ, Gillingwater TH. UBA1: at the crossroads of ubiquitin homeostasis and neurodegeneration. Trends Mol Med
2015; 21: 622–32.
Wang YC, Lauwers E, Verstreken P. Presynaptic protein homeostasis and neuronal function. Curr Opin Genet Dev
2017; 44: 38–46.
Howard SR. Genes underlying delayed puberty. Mol Cell Endocrinol
2018; 476: 119–28.
Han JC, Reyes-Capo DP, Liu CY, Reynolds JC, Turkbey E, et al
. Comprehensive endocrine-metabolic evaluation of patients with alström syndrome compared with BMI-matched controls. J Clin Endocrinol Metab
2018; 103: 2707–19.
Hayer SN, Deconinck T, Bender B, Smets K, Zuchner S, et al
mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations. Orphanet J Rare Dis
2018; 12: 31.
Hoffmann HM, Mellon PL. Regulation of GnRH gene expression. In: Herbison AE, Plant TM, editors. GnRH Neuron and Its Control. Chichester: Wiley Blackwell; 2018. p95–119.
Bjelobaba I, Stojilkovic SS, Naor Z. Editorial: gonadotropin-releasing hormone receptor signalling and functions. Front Endocrinol
2018; 9: 1–3.
McCartney CR, Marshall JC. Neuroendocrinology of reproduction. In: Strauss J, Barbieri R, Gargiulo A, editors. Yen and Jaffe's Reproductive Endocrinology. 8th
ed. Cambridge: Elsevier; 2019. p1–24.
Choe HK, Kim HD, Park SH, Lee HW, Park JY, et al
. Synchronous activation of gonadotropin-releasing hormone gene transcription and secretion by pulsatile kisspeptin stimulation. Proc Natl Acad Sci U S A
2013; 110: 5677–82.
Candlish M, Wartenberg P, Boehm U. Genetic strategies examining kisspeptin regulation of GnRH neurons. In: Herbison AE, Plant TM, editors. GnRH Neuron and Its Control. Chichester: Wiley Blackwell; 2018. p259–87.
Howard SR. Genetic regulation in pubertal delay. J Mol Endocrinol
2019; 63: R37–49.
Todman MG, Han SK, Herbison AE. Profiling neurotransmitter receptor expression in mouse gonadotropin-releasing hormone neurons using green fluorescent protein-promoter transgenics and microarrays. Neurosci
2005; 132: 703–12.
Giacobini P, Kopin AS, Beart PM, Mercer LD, Fasolo A, et al
. Cholecystokinin modulates migration of gonadotropin-releasing hormone-1 neurons. J Neurosci
2004; 24: 4737–48.
Temple JL, Wray S. Developmental changes in GABA receptor subunit composition within the gonadotrophin-releasing hormone-1 neuronal system. J Neuroendocrinol
2005; 17: 591–9.
Lucas-Herald A, Bertelloni S, Juul A, Bryce J, Jiang J, et al
. The long-term outcome of boys with partial androgen insensitivity syndrome and a mutation in the androgen receptor gene. J Clin Endocrinol Metab
2016; 101: 3959–67.
Dinasarapu AR, Saunders B, Ozerlat I, Azam K, Subramaniam S. Signalling gateway molecule pages – a data model perspective. Bioinformatics
2011; 27: 1736–8.
Ritter SL, Hall RA. Fine-tuning of GPCR activity by receptor-interacting proteins. Nat Rev Mol Cell Biol
2009; 10: 819–30.
Zhao J, Deng Y, Jiang Z, Qing H. G protein-coupled receptors (GPCRs) in Alzheimer's disease: a focus on BACE1 related GPCRs. Front Aging Neurosci
2016; 8: 58.
Zeitlin R, Patel S, Burgess S, Arendash GW, Echeverria V. Caffeine induces beneficial changes in PKA signalling and JNK and ERK activities in the striatum and cortex of Alzheimer's transgenic mice. Brain Res
2011; 1417: 127–36.
New DC, Wong YH. Molecular mechanisms mediating the G protein-coupled receptor regulation of cell cycle progression. J Mol Signal
2007; 2: 2.
Arendash GW, Schleif W, Rezai-Zadeh K, Jackson EK, Zacharia LC, et al
. Caffeine protects Alzheimer's mice against cognitive impairment and reduces brain beta-amyloid production. Neurosci
2006; 142: 941–52.
Sayas CL, Avila J, Wandosell F. Glycogen synthase kinase-3 is activated in neuronal cells by Gα12
by Rho-independent and Rho-dependent mechanisms. J Neurosci
2002; 22: 6863–75.
Ly PT, Wu YL, Zou HY, Wang RT, Zhou WH, et al
. Inhibition of GSK3 β-mediated BACE1 expression reduces Alzheimer-associated phenotypes. J Clin Invest
2013; 123: 224–35.
Schlessinger J. Cell signalling by receptor tyrosine kinases. Cell
2000; 103: 211–25.
Hubbard SR. Juxtamembrane autoinhibition in receptor tyrosine kinases. Nat Rev Mol Cell Biol
2004; 5: 464–71.
Guo H, Barrett TM, Zhong Z, Fernández JA, Griffin JH, et al
. Protein S blocks the extrinsic apoptotic cascade in tissue plasminogen activator/N-methyl D-aspartate-treated neurons via Tyro3-Akt-FKHRL1 signalling pathway. Mol Neurodegener
2011; 6: 13.
Zhang J, Qi X. The role of the TAM family of receptor tyrosine kinases in neural development and disorders. Neuropsychiatry
2018; 8: 428–37.
Allen MP, Xu M, Linseman DA, Pawlowski JE, Bokoch GM, et al
. Adhesion-related kinase repression of gonadotropin-releasing hormone gene expression requires Rac activation of the extracellular signal-regulated kinase pathway. J Biol Chem
2002; 277: 38133–40.
Zhou Y, Gunput RF, Pasterkamp RJ. Semaphorin signalling: progress made and promises ahead. Trends Biochem Sci
2008; 33: 161–70.
Oleari R, Lettieri A, Paganoni A, Zanieri L, Cariboni A. Semaphorin signalling in GnRH neurons: from development to disease. Neuroendocrinology
2019; 109: 193–9.
Constantin S, Caligioni CS, Stojilkovic S, Wray S. Kisspeptin-10 facilitates a plasma membrane driven calcium oscillator in GnRH-1 neurons. Endocrinology
2009; 150: 1400–12.
Xu R, Feng J, Liang C, Song G, Yan Y. Effects of High-Fat Diet and Treadmill Running on the Hypothalamic Kiss-1-GPR54 Signalling Pathway in Growing Male Rats; 2021. Available from: https://doi.org/10.21203/rs.3.rs-717653/v1
. [Last accessed on 2021 Dec 01].
Klenke U, Constantin S, Wray S. Neuropeptide Y directly inhibits neuronal activity in a subpopulation of gonadotropin-releasing hormone-1 neurons via Y1 receptors. Endocrinology
2010; 151: 2736–46.
Li E, Hristova K. Role of receptor tyrosine kinase transmembrane domains in cell signalling and human pathologies. Biochemistry
2006; 45: 6241–51.
Stopa EG, Koh ET, Svendsen CN, Rogers WT, Schwaber JS, et al
. Computer-assisted mapping of immunoreactive mammalian gonadotropin-releasing hormone in adult human basal forebrain and amygdala. Endocrinology
1991; 128: 3199–207.
Xue H, Gai X, Sun W, Li C, Liu Q. Morphological changes of gonadotropin-releasing hormone neurons in the rat preoptic area across puberty. Neural Regen Res
2014; 9: 1303–12.
Burgus R, Butcher M, Amoss M, Ling N, Monahan M, et al
. Primary structure of the ovine hypothalamic luteinizing hormone-releasing factor (LRF) (LH-hypothalamus-LRF-gas chromatography-mass spectrometry-decapeptide-Edman degradation). Proc Natl Acad Sci U S A
1972; 69: 278–82.
Lawson MA, Macconell LA, Kim J, Powl BT, Nelson SB, et al
. Neuron-specific expression in vivo
by defined transcription regulatory elements of the gonadotropin-releasing hormone gene. Endocrinology
2002; 143: 1404–12.
Clark ME, Mellon PL. The POU homeodomain transcription factor Oct-1 is essential for activity of the gonadotropin-releasing hormone neuron-specific enhancer. Mol Cell Biol 1995; 15: 6169–77.
Skrapits K, Hrabovszky E. The anatomy of the GnRH neuron network in the human. In: Herbison AE, Plant TM, editors. GnRH Neuron and Its Control. Chichester: Wiley Blackwell; 2018. p149–75.
Diaczok D, DiVall S, Matsuo I, Wondisford FE, Wolfe AM, et al
. Deletion of Otx2
in GnRH neurons results in a mouse model of hypogonadotropic hypogonadism. Mol Endocrinol
2011; 25: 833–46.
Vazquez-Martinez R, Shorte SL, Boockfor FR, Frawley LS. Synchronized exocytotic bursts from gonadotropin-releasing hormone-expressing cells: dual control by intrinsic cellular pulsatility and gap junctional communication. Endocrinology
2001; 142: 2095–101.
Pratap A, Garner KL, Voliotis M, Tsaneva-Atanasova K, McArdle CA. Mathematical modeling of gonadotropin-releasing hormone signalling. Mol Cell Endocrinol
2017; 449: 42–55.
Armstrong SP, Caunt CJ, Fowkes RC, Tsaneva-Atanasova K, McArdle CA. Pulsatile and sustained gonadotropin-releasing hormone (GnRH) receptor signalling: does the ERK signalling pathway decode GnRH pulse frequency? J Biol Chem
2010; 285: 24360–71.
Stamatiades GA, Kaiser UB. Gonadotropin regulation by pulsatile GnRH: signalling and gene expression. Mol Cell Endocrinol
2018; 463: 131–41.
Pincus SM, Padmanabhan V, Lemon W, Randolph J, Midgley AR. Follicle-stimulating hormone is secreted more irregularly than luteinizing hormone in both humans and sheep. J Clin Invest
1998; 101: 1318–24.
Day FR, Bulik-Sullivan B, Hinds DA, Finucane HK, Murabito JM, et al
. Shared genetic aetiology of puberty timing between sexes and with health-related outcomes. Nat Commun
2015; 6: 8842.
Hu SC, Ye J, Fathi AK, Fu X, Huang S, et al
. Mutations in NR5A1 and PIN1 associated with idiopathic hypogonadotropic hypogonadism. Genet Mol Res
2012; 11: 4575–84.
Gill ME, Hu YC, Lin Y, Page DC. Licensing of gametogenesis, dependent on RNA binding protein DAZL, as a gateway to sexual differentiation of fetal germ cells. Proc Natl Acad Sci U S A
2011; 108: 7443–8.
Gubbay J, Collignon J, Koopman P, Capel B, Economou A, et al
. A gene mapping to the sex-determining region of the mouse Y chromosome is a member of a novel family of embryonically expressed genes. Nature
1990; 346: 245–50.
Sekido R, Lovell-Badge R. Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer. Nature
2008; 453: 930–4.
Warr N, Greenfield A. The molecular and cellular basis of gonadal sex reversal in mice and humans. Wiley Interdiscip Rev Dev Biol
2012; 1: 559–77.
Larney C, Bailey TL, Koopman P. Switching on sex: transcriptional regulation of the testis-determining gene Sry
2014; 141: 2195–205.
Hutson JM, Li R, Southwell BR, Newgreen D, Cousinery M. Regulation of testicular descent. Pediatr Surg Int
2015; 31: 317–25.
Mäkelä J, Koskenniemi JJ, Virtanen HE, Toppari J. Testis development. Endocr Rev
2019; 40: 857–905.
Fabbri-Scallet H, de Sousa LM, Maciel-Guerra AT, Guerra-Junior G, de Mello MP. Mutation update for the NR5A1
gene involved in DSD and infertility. Hum Mutat
2020; 41: 58–68.
El-Houate B, Rouba H, Sibai H, Barakat A, Chafik A, et al
. Novel mutations involving the INSL3
gene associated with cryptorchidism. J Urol
2007; 177: 1947–51.
Liu S, Yan L, Zhou X, Chen C, Wang D, et al
. Delayed-onset adrenal hypoplasia congenita and hypogonadotropic hypogonadism caused by a novel mutation in DAX1. J Int Med Res
2020; 48: 0300060519882151.
Kaprara A, Huhtaniemi IT. The hypothalamus-pituitary-gonad axis: tales of mice and men. Metabolism
2017; 86: 3–17.
Gilchrist RL, Ryu KS, Ji I, Ji TH. The luteinizing hormone/chorionic gonadotropin receptor has distinct transmembrane conductors for cAMP and inositol phosphate signals. J Biol Chem
1996; 271: 19283–7.
Choi J, Smitz J. Luteinizing hormone and human chorionic gonadotropin: origins of difference. Mol Cell Endocrinol
2014; 383: 203–13.
Shiraishi K, Ascoli M. Lutropin/choriogonadotropin stimulate the proliferation of primary cultures of rat Leydig cells through a pathway that involves activation of the extracellularly regulated kinase 1/2 cascade. Endocrinology
2007; 148: 3214–25.
Brown C, LaRocca J, Pietruska J, Ota M, Anderson L, et al
. Subfertility caused by altered follicular development and oocyte growth in female mice lacking PKB alpha/Akt1. Biol Reprod
2010; 82: 246–56.
Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev
2011; 32: 81–151.
Fluck CE, Pandey AV. Testicular steroidogenesis. In: Simoni M, Huhtaniemi I, editors. Endocrinology of the Testis and Male Reproduction. Gewerbestrasse: Springer; 2017. p339–67.
Fevold HR, Lorence MC, McCarthy JL, Trant JM, Kagimoto M, et al
. Rat P450(17 alpha) from testis: characterization of a full-length cDNA encoding a unique steroid hydroxylase capable of catalyzing both delta 4- and delta 5-steroid-17,20-lyase reactions. Mol Endocrinol
1989; 3: 968–75.
Strott CA. Steroid sulfotransferases. Endocr Rev
1996; 17: 670–97.
Fluck CE, Pandey AV. Steroidogenesis of the testis – new genes and pathways. Ann Endocrinol
2014; 75: 40–7.
Newton CL, Anderson RC, Katz AA, Millar RP. Loss-of-function mutations in the human luteinizing hormone receptor predominantly cause intracellular retention. Endocrinology
2016; 157: 4364–77.
Quigley CA, De Bellis A, Marschke KB, El-Awady MK, Wilson EM, et al
. Androgen receptor defects: historical, clinical, and molecular perspectives. Endocr Rev
1995; 16: 271–321.
Davey RA, Grossmann M. Androgen receptor structure, function and biology: from bench to bedside. Clin Biochem Rev
2016; 37: 3–15.
van de Wijngaart DJ, Dubbink HJ, van Royen ME, Trapman J, Jenster G. Androgen receptor coregulators: recruitment via the coactivator binding groove. Mol Cell Endocrinol
2012; 352: 57–69.
Loss ES, Jacobsen M, Costa ZS, Jacobus AP, Borelli F, et al
. Testosterone modulates K+
ATP channels in Sertoli cell membrane via the PLC-PIP2
pathway. Horm Metab Res
2004; 36: 519–25.
Leung JK, Sadar MD. Non-genomic actions of the androgen receptor in prostate cancer. Front Endocrinol
2017; 8: 2.
Heinlein CA, Chang C. Androgen receptor (AR) coregulators: an overview. Endocr Rev
2002; 23: 175–200.
Heemers HV, Tindall DJ. Androgen receptor (AR) coregulators: a diversity of functions converging on and regulating the AR transcriptional complex. Endocr Rev
2007; 28: 778–808.
Di Donato M, Bilancio A, D'Amato L, Claudiani P, Oliviero MA, et al
. Cross-talk between androgen receptor/filamin A and TrkA regulates neurite outgrowth in PC12 cells. Mol Biol Cell
2015; 26: 2858–72.
Carrera-Garcia L, Rivas-Crespo MF, Garcia MS. Androgen receptor dysfunction as a prevalent manifestation in young male carriers of a FLNA
gene mutation. Am J Med Genet
2017; 173A: 1710–3.
Nathan BM, Palmert MR. Regulation and disorders of pubertal timing. Endocrinol Metab Clin North Am
2005; 34: 617–41.
Chan YM. Effects of kisspeptin on hormone secretion in humans. Adv Exp Med Biol
2013; 784: 89–112.
Young J, Xu C, Papadakis GE, Acierno JS, Maione L, et al
. Clinical management of congenital hypogonadotropic hypogonadism. Endocr Rev
2019; 40: 669–710.
Kanzi AM, San JE, Chimukangara B, Wilkinson E, Fish M, et al
. Next generation sequencing and bioinformatics analysis of family genetic inheritance. Front Genet
2020; 11: 544162.
Matsuo T, Okamoto S, Izumi Y, Hosokawa A, Takegawa T, et al
. A novel mutation of the KAL1
gene in monozygotic twins with Kallmann syndrome. Eur J Endocrinol
2000; 143: 783–7.
Atchison FW, Means AR. Spermatogonial depletion in adult Pin1
-deficient mice. Biol Reprod
2003; 69: 1989–97.
Zhao L, Bakke M, Parker KL. Pituitary-specific knockout of steroidogenic factor 1. Mol Cell Endocrinol
2001; 185: 27–32.
Lu PJ, Zhou XZ, Liou YC, Noel JP, Lu KP. Critical role of WW domain phosphorylation in regulating phosphoserine binding activity and Pin1 function. J Biol Chem
2002; 277: 2381–4.
Chen WY, Weng JH, Huang CC, Chung BC. Histone deacetylase inhibitors reduce steroidogenesis through SCF-mediated ubiquitination and degradation of steroidogenic factor 1 (NR5A1). Mol Cell Biol
2007; 27: 7284–90.
Benayoun BA, Veitia RA. A post-translational modification code for transcription factors: sorting through a sea of signals. Trends Cell Biol
2009; 19: 189–97.
Nakamura K, Kosugi I, Lee DY, Hafner A, Sinclair DA, et al
. Prolyl isomerase Pin1 regulates neuronal differentiation via β-Catenin. Mol Cell Biol
2012; 32: 2966–78.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]