scholarly journals Olfactory and vomeronasal innervation of the olfactory bulbs are not essential for GnRH-1 neuronal migration to the brain

2017 ◽  
Author(s):  
Ed Zandro Taroc ◽  
Aparna Prasad ◽  
Jennifer M. Lin ◽  
Paolo E. Forni
Keyword(s):  
Cell Migration ◽  
Embryonic Development ◽  
Sensory Neurons ◽  
Neuronal Migration ◽  
Hypogonadotropic Hypogonadism ◽  
Gonadotropin Releasing Hormone ◽  
Olfactory Bulbs ◽  
The Brain ◽  
Olfactory Pit ◽  
Vomeronasal Sensory Neurons

AbstractGonadotropin releasing hormone-1 (GnRH-1) neurons migrate from the developing olfactory pit into the hypothalamus during embryonic development. Migration of the GnRH-1 neurons is required for mammalian reproduction as these cells control release of gonadotropins from the anterior pituitary gland. Disturbances in GnRH-1 cell migration, GnRH-1 synthesis, secretion or signaling lead to varying degrees of hypogonadotropic hypogonadism (HH), which impairs pubertal onset and fertility. HH associated with congenital olfactory defects is clinically defined as Kallmann Syndrome (KS).The association of olfactory defects with HH in KS suggested potential direct relationship between defective olfactory axonal routing, lack of olfactory bulbs and aberrant GnRH-1 cell migration. However, it has never been experimentally proven that the formation of axonal connections of the olfactory and vomeronasal neurons to their functional targets are necessary for the migration GnRH-1 neurons to the hypothalamus. Loss-of-function of the Arx-1 homeobox gene leads to the lack of proper formation of the olfactory bulbs with abnormal axonal termination of olfactory sensory neurons (Yoshihara et al., 2005). We exploited the Arx-1null mouse line to investigate the role of the olfactory system (olfactory/vomeronasal fibers and OBs) in controlling GnRH-1 migration to the hypothalamus. Our data proves that correct development of the OBs, and axonal connection of the olfactory and vomeronasal sensory neurons to the forebrain are not needed for GnRH-1 neuronal migration. Moreover, we prove that the terminal nerve, which forms the GnRH-1 migratory scaffold, follows different guidance cues and differs in its genetic expression from olfactory and vomeronasal sensory neurons.Significance StatementGonadotropin Releasing Hormone-1 (GnRH-1) neurons control the reproductive axis of vertebrates. During embryonic development, these neurons migrate from the olfactory pit to the hypothalamus. GnRH-1 cell migration is commonly believed to take place along the olfactory axons. Our work reveals that correct olfactory bulb development and targeting of the olfactory and vomeronasal sensory neurons to the brain are not required for this migration. Our work challenges the idea that GnRH-1 neuronal migration to the hypothalamus relies on correct routing of the olfactory and vomeronasal sensory neurons. We provide a new basis for interpreting genetic correlations between anosmia, lack of olfactory bulbs, and hypogonadotropic hypogonadism in Kallmann Syndrome.

scholarly journals Kallmann syndrome and ichthyosis: a case of contiguous gene deletion syndrome

2017 ◽  
Vol 2017 ◽  
Author(s):  
Irene Berges-Raso ◽  
Olga Giménez-Palop ◽  
Elisabeth Gabau ◽  
Ismael Capel ◽  
Assumpta Caixàs ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Hypogonadotropic Hypogonadism ◽  
Kallmann Syndrome ◽  
Gonadotropin Releasing Hormone ◽  
Sex Characteristics ◽  
Steroid Sulfatase ◽  
Olfactory Bulbs ◽  
Releasing Hormone ◽  
Secondary Sex Characteristics ◽  
Contiguous Gene

Summary Kallmann syndrome is a genetically heterogeneous form of hypogonadotropic hypogonadism caused by gonadotropin-releasing hormone deficiency and characterized by anosmia or hyposmia due to hypoplasia of the olfactory bulbs; osteoporosis and metabolic syndrome can develop due to longstanding untreated hypogonadism. Kallmann syndrome affects 1 in 10 000 men and 1 in 50 000 women. Defects in 17 genes, including KAL1, have been implicated. Kallmann syndrome can be associated with X-linked ichthyosis, a skin disorder characterized by early onset dark, dry, irregular scales affecting the limb and trunk, caused by a defect of the steroid sulfatase gene (STS). Both KAL1 and STS are located in the Xp22.3 region; therefore, deletions in this region cause a contiguous gene syndrome. We report the case of a 32-year-old man with ichthyosis referred for evaluation of excessive height (2.07 m) and weight (BMI: 29.6 kg/m2), microgenitalia and absence of secondary sex characteristics. We diagnosed Kallmann syndrome with ichthyosis due to a deletion in Xp22.3, a rare phenomenon. Learning points: Kallmann syndrome is a genetically heterogeneous disease characterized by hypogonadotropic hypogonadism with anosmia or hyposmia associated with defects in the production or action of gonadotropin-releasing hormone (GnRH) and hypoplasia of the olfactory bulbs. Several genes have been implicated in Kallmann syndrome, including KAL1, located in the Xp22.3 region, which is responsible for X-linked Kallmann syndrome. KAL1 encodes the protein anosmin-1. X-linked ichthyosis is caused by deficiency of the steroid sulfatase enzyme, encoded by STS, which is also located in the Xp22.3 region. Deletions involving this region can affect both genes and result in contiguous gene syndromes. Phenotype can guide clinicians toward suspicion of a specific genetic mutation. KAL1 mutations are mostly related to microgenitalia, unilateral renal agenesis and synkinesia, although patients need not present all these abnormalities. Longstanding untreated hypogonadism is associated with poor sexual health, osteoporosis and metabolic syndrome with the concomitant risk of developing type 2 diabetes mellitus and obesity. Treatment aims to promote the development of secondary sex characteristics, build and sustain normal bone and muscle mass and restore fertility. Treatment can also help minimize some psychological consequences. Treatments available for patients with congenital GnRH deficiency such as Kallmann syndrome include gonadal steroid hormones, human gonadotropins and GnRH. The choice of therapy depends on the goal or goals.

scholarly journals A case of Kallmann syndrome associated with a non-functional pituitary microadenoma

2018 ◽  
Vol 2018 ◽  
Author(s):  
Taieb Ach ◽  
Hela Marmouch ◽  
Dorra Elguiche ◽  
Asma Achour ◽  
Hajer Marzouk ◽  
...  
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Pubic Hair ◽  
Empty Sella ◽  
Kallmann Syndrome ◽  
List Type ◽  
Olfactory Bulbs ◽  
Empty Sella Syndrome ◽  
Pituitary Microadenoma ◽  
Pituitary Hypoplasia ◽  
The Brain

Summary Kallmann syndrome (KS) is a form of hypogonadotropic hypogonadism in combination with a defect in sense of smell, due to abnormal migration of gonadotropin-releasing hormone-producing neurons. We report a case of a 17-year-old Tunisian male who presented with eunuchoid body proportions, absence of facial, axillary and pubic hair, micropenis and surgically corrected cryptorchidism. Associated findings included anosmia. Karyotype was 46XY and hormonal measurement hypogonadotropic hypogonadism. MRI of the brain showed bilateral agenesis of the olfactory bulbs and 3.5 mm pituitary microadenoma. Hormonal assays showed no evidence of pituitary hypersecretion. Learning points: The main clinical characteristics of KS include hypogonadotropic hypogonadism and anosmia or hyposmia. MRI, as a non-irradiating technique, should be the first radiological step for investigating the pituitary gland as well as abnormalities of the ethmoid, olfactory bulbs and tracts in KS. KS may include anterior pituitary hypoplasia or an empty sella syndrome. The originality of our case is that a microadenoma also may be encountered in KS. Hormonal assessment indicated the microadenoma was non-functioning. This emphasizes the importance of visualizing the pituitary region in KS patients to assess for hypoplastic pituitary malformations or adenomas.

scholarly journals Defects in the GnRH Neuronal Migration factor, CCDC141, Lead to Self-Limited Delayed Puberty

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A665-A666
Author(s):  
Tansit Saengkaew ◽  
Alessandra Mancini ◽  
Gerard Ruiz-Babot ◽  
Claudia P Cabrera ◽  
Michael R Barnes ◽  
...  
Keyword(s):  
Cell Migration ◽  
Neuronal Migration ◽  
Hypogonadotropic Hypogonadism ◽  
Hek293 Cells ◽  
Delayed Puberty ◽  
Compound Heterozygous ◽  
Critical Element ◽  
Incomplete Penetrance ◽  
Inheritance Pattern ◽  
Foetal Development

Abstract GnRH neuronal biology has been identified as a critical element in the pathogenesis of self-limited DP, previously implicated exclusively in the pathophysiology of idiopathic hypogonadotropic hypogonadism (IHH). We hypothesise that this condition may be inherited via genetic variants discoverable through whole-exome sequencing (WES), by focusing on genes involved in GnRH neuron development and function, and genes reported in IHH. We analysed WES data from large Finnish cohort with familial self-limited DP, focusing on genes recently reported in IHH. WES data of 100 DP families have been analysed with a total of 193 individuals: 100 probands, 158 affected and 35 unaffected family members. Potentially pathogenic rare variants segregating within cohort families were identified using a virtual panel of recently reported IHH genes (n=13). This analysis identified 6 rare potentially pathogenic variants in CCDC141 in 25 individuals of 8 families which account for almost 10% of self-limited DP cases in this cohort, without variants identified in cohort control cases. Previous studies reported that homozygous or compound heterozygous mutations of CCDC141 cause Kallmann syndrome and IHH, due to impaired GnRH neuronal migration. In this study, all 6 CCDC141 variants were heterozygous missense variants predicted to be deleterious by in silico prediction tools. Most probands were male (n=7) with typical features of self-limited DP, with absence of secondary sexual characteristics, delayed bone age, and low gonadotropins and sex steroids at first presentation and spontaneous entry into puberty later than age of 14 years without treatment. The majority of pedigrees displayed good segregation of variants with the DP trait, following an autosomal dominant inheritance pattern. However, in two families, there was a complex inheritance pattern with compound heterozygosity (p.Ser55Cys and p.Asp767Asn) and possible incomplete penetrance. In vitro study showed that the overexpression of four key CCDC141 variants in HEK293 cells delayed cell migration, 72% in p.Ser55Cys (p=0.04), 66% in p.Gln507His (p=0.04), 65% in p.Asp767Asn (p=0.02), and 83% in p.Ala1073Thr (p=0.01), when compared to WT (100%). Moreover, WT-overexpressed cells increased the rate of cell migration when compared to non-transfected cells (100% vs 65%, p=0.005), reaffirming that CCDC141 has a role in cell migration. In conclusion, heterozygous deficiency of CCDC141, previously reported to cause IHH, can cause self-limited DP due to abnormal GnRH migration during foetal development.

scholarly journals Molecular clues in the regulation of mini‐puberty involve neuronal DNA binding transcription factor NHLH2

2021 ◽  
Vol 31 (1) ◽  
Author(s):  
Faruk Hadziselimovic ◽  
Gilvydas Verkauskas ◽  
Michael B. Stadler
Keyword(s):  
Target Genes ◽  
Hypogonadotropic Hypogonadism ◽  
Mrna Level ◽  
Hormone Treatment ◽  
Gonadotropin Releasing Hormone ◽  
Expression Levels ◽  
Rna Profiling ◽  
Gonadotropin Releasing Hormone Agonist ◽  
Helix Loop Helix ◽  
The Brain

AbstractGonadotropin releasing hormone agonist (GnRHa) treatment following surgery to correct cryptorchidism restores mini-puberty via endocrinological and transcriptional effects and prevents adult infertility in most cases. Several genes are important for central hypogonadotropic hypogonadism in mammals, including many that are transcribed in both the brain and testis. However, the expression of these genes in prepubertal gonads has not been studied systematically, and little is known about the effect of hormone therapy on their testicular and neuronal expression levels. In this review, we interpret histological sections, data on hormone levels, and RNA profiling data from adult normal testes compared to pre-pubertal low infertility risk (LIR) and high infertility risk (HIR) patients randomly treated with surgery in combination with GnRHa or only surgery. We organize 31 target genes relevant for idiopathic hypogonadotropic hypogonadism and cryptorchidism into five classes depending on their expression levels in HIR versus LIR samples and their response to GnRHa treatment. Nescient-helix-loop-helix 2 (NHLH2) was the only gene showing a decreased mRNA level in HIR patients and an increase after GnRHa treatment. This phenomenon may reflect a broader effect of hormone treatment on gene expression in both testicular and central nervous system tissues, which could explain why the hypothalamus-pituitary-testicular axis is permanently restored by the administration of GnRHa.

Glucuronyl 3-sulfate occurs exclusively on distal unmyelinated terminals of selected sensory neurons in the peripheral nervous system

1995 ◽  
Vol 53 ◽  
pp. 958-959
Author(s):  
S.S. Spicer ◽  
B.A. Schulte
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cerebral Cortex ◽  
Peripheral Nervous System ◽  
Sensory Neurons ◽  
Sensory Nerves ◽  
Tissue Antigens ◽  
The Central Nervous System ◽  
The Brain ◽  
Leu 7

Generation of monoclonal antibodies (MAbs) against tissue antigens has yielded several (VC1.1, HNK- 1, L2, 4F4 and anti-leu 7) which recognize the unique sugar epitope, glucuronyl 3-sulfate (Glc A3- SO4). In the central nervous system, these MAbs have demonstrated Glc A3-SO4 at the surface of neurons in the cerebral cortex, the cerebellum, the retina and other widespread regions of the brain.Here we describe the distribution of Glc A3-SO4 in the peripheral nervous system as determined by immunostaining with a MAb (VC 1.1) developed against antigen in the cat visual cortex. Outside the central nervous system, immunoreactivity was observed only in peripheral terminals of selected sensory nerves conducting transduction signals for touch, hearing, balance and taste. On the glassy membrane of the sinus hair in murine nasal skin, just deep to the ringwurt, VC 1.1 delineated an intensely stained, plaque-like area (Fig. 1). This previously unrecognized structure of the nasal vibrissae presumably serves as a tactile end organ and to our knowledge is not demonstrable by means other than its selective immunopositivity with VC1.1 and its appearance as a densely fibrillar area in H&E stained sections.

scholarly journals Drosophila immune cell migration and adhesion during embryonic development and larval immune responses

2015 ◽  
Vol 36 ◽  
pp. 71-79 ◽  
Author(s):  
Aparna Ratheesh ◽  
Vera Belyaeva ◽  
Daria E Siekhaus
Keyword(s):  
Cell Migration ◽  
Embryonic Development ◽  
Immune Responses ◽  
Immune Cell ◽  
Immune Cell Migration

Bioactive forms of gonadotropin releasing hormone in the brain of an Indian major carp,Catla catla (Ham.)

1995 ◽  
Vol 20 (4) ◽  
pp. 551-561
Author(s):  
S. Halder ◽  
P. Roy ◽  
A. Chatterjee ◽  
S. Bhattacharya
Keyword(s):  
Gonadotropin Releasing Hormone ◽  
Catla Catla ◽  
Indian Major Carp ◽  
Releasing Hormone ◽  
The Brain

A man with hypogonadotropic hypogonadism successfully treated with nasal administration of the low-dose gonadotropin-releasing hormone analog buserelin

2009 ◽  
Vol 92 (3) ◽  
pp. 1169.e1-1169.e3 ◽  
Author(s):  
Hideki Iwamoto ◽  
Atsumi Yoshida ◽  
Hiroki Suzuki ◽  
Miho Tanaka ◽  
Noriko Watanabe ◽  
...  
Keyword(s):  
Low Dose ◽  
Hypogonadotropic Hypogonadism ◽  
Gonadotropin Releasing Hormone ◽  
Nasal Administration ◽  
Releasing Hormone ◽  
Hormone Analog
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