Valproic acid exposure affects social visual lateralization and asymmetric gene expression in zebrafish larvae.

Cerebral asymmetry is critical for typical brain function and development; at the same time, altered brain lateralization seems to be associated with neuropsychiatric disorders. Zebrafish are increasingly emerging as model species to study brain lateralization, using asymmetric development of the habenula, a phylogenetically old brain structure associated with social and emotional processing, to investigate the relationship between brain asymmetry and social behavior. We exposed 5-h post-fertilization zebrafish embryos to valproic acid (VPA), a compound used to model the core signs of ASD in many vertebrate species, and assessed social interaction, visual lateralization and gene expression in the thalamus and the telencephalon. VPA-exposed zebrafish exhibit social deficits and a deconstruction of social visual laterality to the mirror. We also observe changes in the asymmetric expression of the epithalamic marker leftover and in the size of the dorsolateral part of the habenula in adult zebrafish. Our data indicate that VPA exposure neutralizes the animals' visual field bias, with a complete loss of the left-eye use bias in front of their own mirror image, and alters brain asymmetric gene expression and morphology, opening new perspectives to investigate brain lateralization and its link to atypical social cognitive development.

Septostomy and Monroplasty in Isolated Lateral Ventricle After Removal of a Third Ventricle Colloid Cyst: 2-Dimensional Operative Video.

Isolated unilateral hydrocephalus (IUH) is a condition caused by unilateral obstruction of the foramen of Monro.1 Etiopathogenic causes include tumors, congenital lesions, infective ventriculitis, intraventricular haemorrhage, and iatrogenic causes such as the presence of contralateral shunts.2,3 Neuroendoscopic management is considered the "gold-standard" treatment in IUH.4 Even if endoscopic septostomy and foraminoplasty in IUH are well-known procedures,5,6 IUH after an interhemispheric transcallosal transchoroidal approach for removal of a III ventricle colloid cyst is a complication barely described in literature. Video 1 describes this rare complication and the neuroendoscopic treatment adopted, including the operative room setup, patient's positioning, instrumentation needed, and a series of intraoperative tips for the performance of septostomy and Monroplasty via a single, precoronal burr hole. The scalp entry point and endoscope trajectory, homolateral to the dilated ventricle, were planned on the neuronavigation system. The avascular septal zone away from the septal veins and body of the fornix was reached, and the ostomy was performed. At the end of the procedure, Monroplasty was performed, too. The procedure was effective in solving the hydrocephalus and patient's clinical picture. No surgical complications occurred. Imaging demonstrated an evident and progressive reduction of enlarged lateral ventricle. In authors' opinion, the single burr-hole approach, ipsilateral to the enlarged ventricle, provides an optimal identification the intraventricular anatomy and allows Monroplasty to be performed, if deemed feasible during surgery. The patient consented to the procedure. The participants and any identifiable individuals consented to publication of their images.

Understanding the genetic complexity of puberty timing across the allele frequency spectrum.

Pubertal timing varies considerably and has been associated with a range of health outcomes in later life. To elucidate the underlying biological mechanisms, we performed multi-ancestry genetic analyses in ~800,000 women, identifying 1,080 independent signals associated with age at menarche. Collectively these loci explained 11% of the trait variance in an independent sample, with women at the top and bottom 1% of polygenic risk exhibiting a ~11 and ~14-fold higher risk of delayed and precocious pubertal development, respectively. These common variant analyses were supported by exome sequence analysis of ~220,000 women, identifying several genes, including rare loss of function variants in ZNF483 which abolished the impact of polygenic risk. Next, we implicated 660 genes in pubertal development using a combination of in silico variant-to-gene mapping approaches and integration with dynamic gene expression data from mouse embryonic GnRH neurons. This included an uncharacterized G-protein coupled receptor GPR83, which we demonstrate amplifies signaling of MC3R, a key sensor of nutritional status. Finally, we identified several genes, including ovary-expressed genes involved in DNA damage response that co-localize with signals associated with menopause timing, leading us to hypothesize that the ovarian reserve might signal centrally to trigger puberty. Collectively these findings extend our understanding of the biological complexity of puberty timing and highlight body size dependent and independent mechanisms that potentially link reproductive timing to later life disease.

NOS1 mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits that can be reversed in infantile mice.

The nitric oxide (NO) signaling pathway in hypothalamic neurons plays a key role in the regulation of the secretion of gonadotropin-releasing hormone (GnRH), which is crucial for reproduction. We hypothesized that a disruption of neuronal NO synthase (NOS1) activity underlies some forms of hypogonadotropic hypogonadism. Whole-exome sequencing was performed on a cohort of 341 probands with congenital hypogonadotropic hypogonadism to identify ultrarare variants in NOS1. The activity of the identified NOS1 mutant proteins was assessed by their ability to promote nitrite and cGMP production in vitro. In addition, physiological and pharmacological characterization was carried out in a Nos1-deficient mouse model. We identified five heterozygous NOS1 loss-of-function mutations in six probands with congenital hypogonadotropic hypogonadism (2%), who displayed additional phenotypes including anosmia, hearing loss, and intellectual disability. NOS1 was found to be transiently expressed by GnRH neurons in the nose of both humans and mice, and Nos1 deficiency in mice resulted in dose-dependent defects in sexual maturation as well as in olfaction, hearing, and cognition. The pharmacological inhibition of NO production in postnatal mice revealed a critical time window during which Nos1 activity shaped minipuberty and sexual maturation. Inhaled NO treatment at minipuberty rescued both reproductive and behavioral phenotypes in Nos1-deficient mice. In summary, lack of NOS1 activity led to GnRH deficiency associated with sensory and intellectual comorbidities in humans and mice. NO treatment during minipuberty reversed deficits in sexual maturation, olfaction, and cognition in Nos1 mutant mice, suggesting a potential therapy for humans with NO deficiency.

GnRH replacement rescues cognition in Down syndrome.

At the present time, no viable treatment exists for cognitive and olfactory deficits in Down syndrome (DS). We show in a DS model (Ts65Dn mice) that these progressive nonreproductive neurological symptoms closely parallel a postpubertal decrease in hypothalamic as well as extrahypothalamic expression of a master molecule that controls reproduction-gonadotropin-releasing hormone (GnRH)-and appear related to an imbalance in a microRNA-gene network known to regulate GnRH neuron maturation together with altered hippocampal synaptic transmission. Epigenetic, cellular, chemogenetic, and pharmacological interventions that restore physiological GnRH levels abolish olfactory and cognitive defects in Ts65Dn mice, whereas pulsatile GnRH therapy improves cognition and brain connectivity in adult DS patients. GnRH thus plays a crucial role in olfaction and cognition, and pulsatile GnRH therapy holds promise to improve cognitive deficits in DS.

Quantity as a Fish Views It: Behavior and Neurobiology.

An ability to estimate quantities, such as the number of conspecifics or the size of a predator, has been reported in vertebrates. Fish, in particular zebrafish, may be instrumental in advancing the understanding of magnitude cognition. We review here the behavioral studies that have described the ecological relevance of quantity estimation in fish and the current status of the research aimed at investigating the neurobiological bases of these abilities. By combining behavioral methods with molecular genetics and calcium imaging, the involvement of the retina and the optic tectum has been documented for the estimation of continuous quantities in the larval and adult zebrafish brain, and the contributions of the thalamus and the dorsal-central pallium for discrete magnitude estimation in the adult zebrafish brain. Evidence for basic circuitry can now be complemented and extended to research that make use of transgenic lines to deepen our understanding of quantity cognition at genetic and molecular levels.

Transcriptome profiling of kisspeptin neurons from the mouse arcuate nucleus reveals new mechanisms in estrogenic control of fertility.

Kisspeptin neurons in the mediobasal hypothalamus (MBH) are critical targets of ovarian estrogen feedback regulating mammalian fertility. To reveal molecular mechanisms underlying this signaling, we thoroughly characterized the estrogen-regulated transcriptome of kisspeptin cells from ovariectomized transgenic mice substituted with 17ß-estradiol or vehicle. MBH kisspeptin neurons were harvested using laser-capture microdissection, pooled, and subjected to RNA sequencing. Estrogen treatment significantly (p.adj. < 0.05) up-regulated 1,190 and down-regulated 1,139 transcripts, including transcription factors, neuropeptides, ribosomal and mitochondrial proteins, ion channels, transporters, receptors, and regulatory RNAs. Reduced expression of the excitatory serotonin receptor-4 transcript (Htr4) diminished kisspeptin neuron responsiveness to serotonergic stimulation. Many estrogen-regulated transcripts have been implicated in puberty/fertility disorders. Patients (n = 337) with congenital hypogonadotropic hypogonadism (CHH) showed enrichment of rare variants in putative CHH-candidate genes (e.g., LRP1B, CACNA1G, FNDC3A). Comprehensive characterization of the estrogen-dependent kisspeptin neuron transcriptome sheds light on the molecular mechanisms of ovary-brain communication and informs genetic research on human fertility disorders.

Multimodal evaluation of 19F-BPA internalization in pancreatic cancer cells for boron capture and proton therapy potential applications.

PURPOSE: One of the obstacles to the application of Boron Neutron Capture Therapy (BNCT) and Proton Boron Fusion Therapy (PBFT) concerns the measurement of borated carriers' biodistribution. The objective of the present study was to evaluate the in vitro internalization of the 19F-labelled p-boronophenylalanine (19F-BPA) in the human cancer pancreatic cell line (PANC-1) for the potential application of BNCT and PBFT in pancreatic cancer. The 19F-BPA carrier has the advantage that its bio-distribution may be monitored in vivo using 19F-Nuclear Magnetic Resonance (19F NMR). MATERIALS AND METHODS: The 19F-BPA internalization in PANC-1 cells was evaluated using three independent techniques on cellular samples left in contact with growing medium enriched with 13.6 mM 19F-BPA corresponding to a 11B concentration of 120 ppm: neutron autoradiography, which quantifies boron; liquid chromatography hyphenated to tandem mass spectrometry and UV-Diode Array Detection (UV-DAD), which quantifies 19F-BPA molecule; and 19F NMR spectroscopy, which detects fluorine nuclei. RESULTS: Our studies suggested that 19F-BPA is internalized by PANC-1 cells. The three methods provided consistent results of about 50% internalization fraction at 120 ppm of 11B. Small variations (less than 15%) in internalization fraction are mainly dependent on the proliferation state of the cells. CONCLUSIONS: The ability of 19F NMR spectroscopy to study 19F-BPA internalization was validated by well-established independent techniques. The multimodal approach we used suggests 19F-BPA as a promising BNCT/PBFT carrier for the treatment of pancreatic cancer. Since the quantification is performed at doses useful for BNCT/PBFT, 19F NMR can be envisaged to monitor 19F-BPA bio-distribution during the therapy.

Neurons in the Dorso-Central Division of Zebrafish Pallium Respond to Change in Visual Numerosity.

We found a region of the zebrafish pallium that shows selective activation upon change in the numerosity of visual stimuli. Zebrafish were habituated to sets of small dots that changed in individual size, position, and density, while maintaining their numerousness and overall surface. During dishabituation tests, zebrafish faced a change in number (with the same overall surface), in shape (with the same overall surface and number), or in size (with the same shape and number) of the dots, whereas, in a control group, zebrafish faced the same stimuli as during the habituation. Modulation of the expression of the immediate early genes c-fos and egr-1 and in situ hybridization revealed a selective activation of the caudal part of the dorso-central division of the zebrafish pallium upon change in numerosity. These findings support the existence of an evolutionarily conserved mechanism for approximate magnitude and provide an avenue for understanding its underlying molecular correlates.

The Sense of Number in Fish, with Particular Reference to Its Neurobiological Bases.

It is widely acknowledged that vertebrates can discriminate non-symbolic numerosity using an evolutionarily conserved system dubbed Approximate Number System (ANS). Two main approaches have been used to assess behaviourally numerosity in fish: spontaneous choice tests and operant training procedures. In the first, animals spontaneously choose between sets of biologically-relevant stimuli (e.g., conspecifics, food) differing in quantities (smaller or larger). In the second, animals are trained to associate a numerosity with a reward. Although the ability of fish to discriminate numerosity has been widely documented with these methods, the molecular bases of quantities estimation and ANS are largely unknown. Recently, we combined behavioral tasks with molecular biology assays (e.g c-fos and egr1 and other early genes expression) showing that the thalamus and the caudal region of dorso-central part of the telencephalon seem to be activated upon change in numerousness in visual stimuli. In contrast, the retina and the optic tectum mainly responded to changes in continuous magnitude such as stimulus size. We here provide a review and synthesis of these findings.

Testosterone-induced increase in libido in a patient with a loss-of-function mutation in the AR gene.

SUMMARY: Complete androgen-insensitivity syndrome (CAIS), a disorder of sex development (46,XY DSD), is caused primarily by mutations in the androgen receptor (AR). Gonadectomy is recommended due to the increased risk of gonadoblastoma, however, surgical intervention is often followed by loss of libido. We present a 26-year-old patient with CAIS who underwent gonadectomy followed by a significant decrease in libido, which was improved with testosterone treatment but not with estradiol. Genetic testing was performed and followed by molecular characterization. We found that this patient carried a previously unidentified start loss mutation in the androgen receptor. This variant resulted in an N-terminal truncated protein with an intact DNA binding domain and was confirmed to be loss-of-function in vitro. This unique CAIS case and detailed functional studies raise intriguing questions regarding the relative roles of testosterone and estrogen in libido, and in particular, the potential non-genomic actions of androgens. LEARNING POINTS: N-terminal truncation of androgen receptor can cause androgen-insensitivity syndrome. Surgical removal of testosterone-producing gonads can result in loss of libido. Libido may be improved with testosterone treatment but not with estradiol in some forms of CAIS. A previously unreported AR mutation - p.Glu2_Met190del (c.2T>C) - is found in a CAIS patient and results in blunted AR transcriptional activity under testosterone treatment.

Asymmetric distribution of pallial-expressed genes in zebrafish (Danio rerio).

The left and right distribution of a set of twenty-six genes in the zebrafish pallium was examined by RT-qPCR experiments. The analysis comprised four general pallial markers (eomesa, emx2, emx3 and prox1); eight genes, dapper1, htr3a, htr3b, htr4, id2, ndr2, pkcß and lmo4, that have been described as asymmetric distributed in the brain of mammals (human and mouse); six genes, arrb2, auts2, baiap2, fez1, gap43 and robo1, asymmetrically distributed in the mammalian cortex, that have been associated with autism in humans; and, eight genes, baz1b, fzd9, limk1, tubgcp5, cyfip1, grik1a, nipa1 and nipa2, which have been associated with developmental dyscalculia, a brain disability linked to brain laterality in humans. We found a leftward bias in the expression of 10 genes (dapper1, htr3a, htr3b, htr4, id2, ndr2, pkcß, auts2, baiap2 and grik1a) and a rightward bias for 5 genes (lmo4, arrb2, fez1, gap43, robo1) in agreement with the data reported in mammals. We also found a rightward lateralization for nipa1 and nipa2, whereas the remaining genes (eomesa, emx2, emx3, prox1, baz1b, cyfip1, fzd9, limk1 and tubgpc5) were bilaterally distributed. These findings suggest a basic homology in the asymmetric expression of several pallial vertebrate genes.

Micromolar Valproic Acid Doses Preserve Survival and Induce Molecular Alterations in Neurodevelopmental Genes in Two Strains of Zebrafish Larvae.

Autism spectrum disorders (ASDs) comprise a genetically heterogeneous group of conditions characterized by a multifaceted range of impairments and multifactorial etiology. Epidemiological studies have identified valproic acid (VPA), an anticonvulsant used to treat epilepsy, as an environmental factor for ASDs. Based on these observations, studies using embryonic exposure to VPA have been conducted in many vertebrate species to model ASD. The zebrafish is emerging as a popular model in biomedical research to study the molecular pathways involved in nervous system disorders. VPA exposure in zebrafish larvae has been shown to produce a plethora of effects on social, motor and anxiety behavior, and several genetic pathways altered by VPA have been described. However, the doses and regimen of administration reported in the literature are very heterogenous, creating contradictory results and posing serious limits to the interpretation of VPA action on neurodevelopment. To shed light on the toxic effect of VPA, we tested micromolar concentrations of VPA, using exposure for 24 and 48 h in two different zebrafish strains. Our results show that micromolar doses of VPA mildly affect embryo survival but are sufficient to induce molecular alterations in neurodevelopmental genes previously shown to be influenced by VPA, with substantial differences between strains.

Neuropilin-1 expression in GnRH neurons regulates prepubertal weight gain and sexual attraction.

Hypothalamic neurons expressing gonadotropin-releasing hormone (GnRH), the "master molecule" regulating reproduction and fertility, migrate from their birthplace in the nose to their destination using a system of guidance cues, which include the semaphorins and their receptors, the neuropilins and plexins, among others. Here, we show that selectively deleting neuropilin-1 in new GnRH neurons enhances their survival and migration, resulting in excess neurons in the hypothalamus and in their unusual accumulation in the accessory olfactory bulb, as well as an acceleration of mature patterns of activity. In female mice, these alterations result in early prepubertal weight gain, premature attraction to male odors, and precocious puberty. Our findings suggest that rather than being influenced by peripheral energy state, GnRH neurons themselves, through neuropilin-semaphorin signaling, might engineer the timing of puberty by regulating peripheral adiposity and behavioral switches, thus acting as a bridge between the reproductive and metabolic axes.

Pathogenic mosaic variants in congenital hypogonadotropic hypogonadism.

PURPOSE: Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder resulting in absent puberty and infertility. The genetic architecture is complex with multiple loci involved, variable expressivity, and incomplete penetrance. The majority of cases are sporadic, consistent with a disease affecting fertility. The current study aims to investigate mosaicism as a genetic mechanism for CHH, focusing on de novo rare variants in CHH genes. METHODS: We evaluated 60 trios for de novo rare sequencing variants (RSV) in known CHH genes using exome sequencing. Potential mosaicism was suspected among RSVs with altered allelic ratios and confirmed using customized ultradeep sequencing (UDS) in multiple tissues. RESULTS: Among the 60 trios, 10 probands harbored de novo pathogenic variants in CHH genes. Custom UDS demonstrated that three of these de novo variants were in fact postzygotic mosaicism-two in FGFR1 (p.Leu630Pro and p.Gly348Arg), and one in CHD7 (p.Arg2428*). Statistically significant variation across multiple tissues (DNA from blood, buccal, hair follicle, urine) confirmed their mosaic nature. CONCLUSIONS: We identified a significant number of de novo pathogenic variants in CHH of which a notable number (3/10) exhibited mosaicism. This report of postzygotic mosaicism in CHH patients provides valuable information for accurate genetic counseling.

Trace Element Bioaccumulation in Stone Curlew (Burhinus oedicnemus, Linnaeus, 1758): A Case Study from Sicily (Italy).

: The study aimed to highlight the degree of trace element contamination along three sites of Sicily: the Magnisi peninsula (MP), located in proximity to the Augusta-Priolo-Melilli petrochemical plant; the Ragusa agro-ecosystem (RA), characterized by a rural landscape; and the Gela plain (GP), characterized by intensive agriculture and a disused petrochemical plant. We collected biological samples (abraded back feathers and blood) of the Stone Curlew (Burhinus oedicnemus Linnaeus, 1758) as well as soil samples to determine the trace elements concentrations of As, Cd, Co, Cr, Cu, Hg, Mn, Ni, Pb, Zn, Se and V using ICP-MS analysis. The results found for the three sites show different trends of accumulation, which depend on the different management and geological characteristics of the areas. The Gela plain and Magnisi peninsula showed a higher degree of contamination (As, Co, Cu, Mn and Se for the Gela plain; Pb and Hg for the Magnisi peninsula). Nevertheless, no critical values were found for either the environment-if the results are compared with the legal limits fixed by the Legislative Decree No. 152/2006, approving the Code on the Environment-or for living organisms-if the results are compared with the toxicological thresholds for birds, especially if the short-term exposure results from the blood values are considered. Only the Se levels in animal blood from the RA and GP were found slightly higher than the minimum level required in bird diets. The positive scenario can be attributed on the one hand to the interruptions of emissions of the Gela refinery around 5 years ago, and on the other hand to the more intense and strict controls that are implemented in the area surrounding the petrochemical pole of Augusta-Priolo-Melilli.

Response to change in the number of visual stimuli in zebrafish:A behavioural and molecular study.

Evidence has shown that a variety of vertebrates, including fish, can discriminate collections of visual items on the basis of their numerousness using an evolutionarily conserved system for approximating numerical magnitude (the so-called Approximate Number System, ANS). Here we combine a habituation/dishabituation behavioural task with molecular biology assays to start investigating the neural bases of the ANS in zebrafish. Separate groups of zebrafish underwent a habituation phase with a set of 3 or 9 small red dots, associated with a food reward. The dots changed in size, position and density from trial to trial but maintained their numerousness, and the overall areas of the stimuli was kept constant. During the subsequent dishabituation test, zebrafish faced a change (i) in number (from 3 to 9 or vice versa with the same overall surface), or (ii) in shape (with the same overall surface and number), or (iii) in size (with the same shape and number). A control group of zebrafish was shown the same stimuli as during the habituation. RT-qPCR revealed that the telencephalon and thalamus were characterized by the most consistent modulation of the expression of the immediate early genes c-fos and egr-1 upon change in numerousness; in contrast, the retina and optic tectum responded mainly to changes in stimulus size.

Brain and Behavioral Asymmetry: A Lesson From Fish.

It is widely acknowledged that the left and right hemispheres of human brains display both anatomical and functional asymmetries. For more than a century, brain and behavioral lateralization have been considered a uniquely human feature linked to language and handedness. However, over the past decades this idea has been challenged by an increasing number of studies describing structural asymmetries and lateralized behaviors in non-human species extending from primates to fish. Evidence suggesting that a similar pattern of brain lateralization occurs in all vertebrates, humans included, has allowed the emergence of different model systems to investigate the development of brain asymmetries and their impact on behavior. Among animal models, fish have contributed much to the research on lateralization as several fish species exhibit lateralized behaviors. For instance, behavioral studies have shown that the advantages of having an asymmetric brain, such as the ability of simultaneously processing different information and perform parallel tasks compensate the potential costs associated with poor integration of information between the two hemispheres thus helping to better understand the possible evolutionary significance of lateralization. However, these studies inferred how the two sides of the brains are differentially specialized by measuring the differences in the behavioral responses but did not allow to directly investigate the relation between anatomical and functional asymmetries. With respect to this issue, in recent years zebrafish has become a powerful model to address lateralization at different level of complexity, from genes to neural circuitry and behavior. The possibility of combining genetic manipulation of brain asymmetries with cutting-edge in vivo imaging technique and behavioral tests makes the zebrafish a valuable model to investigate the phylogeny and ontogeny of brain lateralization and its relevance for normal brain function and behavior.

Neuron-Derived Neurotrophic Factor Is Mutated in Congenital Hypogonadotropic Hypogonadism.

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by infertility and the absence of puberty. Defects in GnRH neuron migration or altered GnRH secretion and/or action lead to a severe gonadotropin-releasing hormone (GnRH) deficiency. Given the close developmental association of GnRH neurons with the olfactory primary axons, CHH is often associated with anosmia or hyposmia, in which case it is defined as Kallmann syndrome (KS). The genetics of CHH are heterogeneous, and >40 genes are involved either alone or in combination. Several CHH-related genes controlling GnRH ontogeny encode proteins containing fibronectin-3 (FN3) domains, which are important for brain and neural development. Therefore, we hypothesized that defects in other FN3-superfamily genes would underlie CHH. Next-generation sequencing was performed for 240 CHH unrelated probands and filtered for rare, protein-truncating variants (PTVs) in FN3-superfamily genes. Compared to gnomAD controls the CHH cohort was statistically enriched for PTVs in neuron-derived neurotrophic factor (NDNF) (p = 1.40 × 10-6). Three heterozygous PTVs (p.Lys62∗, p.Tyr128Thrfs∗55, and p.Trp469∗, all absent from the gnomAD database) and an additional heterozygous missense mutation (p.Thr201Ser) were found in four KS probands. Notably, NDNF is expressed along the GnRH neuron migratory route in both mouse embryos and human fetuses and enhances GnRH neuron migration. Further, knock down of the zebrafish ortholog of NDNF resulted in altered GnRH migration. Finally, mice lacking Ndnf showed delayed GnRH neuron migration and altered olfactory axonal projections to the olfactory bulb; both results are consistent with a role of NDNF in GnRH neuron development. Altogether, our results highlight NDNF as a gene involved in the GnRH neuron migration implicated in KS.

Defective AMH signaling disrupts GnRH neuron development and function and contributes to hypogonadotropic hypogonadism.

Congenital hypogonadotropic hypogonadism (CHH) is a condition characterized by absent puberty and infertility due to gonadotropin releasing hormone (GnRH) deficiency, which is often associated with anosmia (Kallmann syndrome, KS). We identified loss-of-function heterozygous mutations in anti-Müllerian hormone (AMH) and its receptor, AMHR2, in 3% of CHH probands using whole-exome sequencing. We showed that during embryonic development, AMH is expressed in migratory GnRH neurons in both mouse and human fetuses and unconvered a novel function of AMH as a pro-motility factor for GnRH neurons. Pathohistological analysis of Amhr2-deficient mice showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in reduced fertility in adults. Our findings highlight a novel role for AMH in the development and function of GnRH neurons and indicate that AMH signaling insufficiency contributes to the pathogenesis of CHH in humans.