The Differential Roles for Neurodevelopmental and Neuroendocrine Genes in Shaping GnRH Neuron Physiology and Deficiency

Oleari, Roberto; Massa, Valentina; Cariboni, Anna; Lettieri, Antonella

doi:10.3390/ijms22179425

Cited by 17 publications

(17 citation statements)

References 242 publications

(327 reference statements)

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“…S3 " type="url"/> ). In our set-up, NRP1 , a gene implicated in the development of CHH ( Men et al, 2021 ; Oleari et al, 2021 ), has shown consistent upregulation upon treatment with FGF8. Interestingly, GnRH neurons in mice have been shown to express Nrp1 ( Vanacker et al, 2020 ), which is known to have a role in the migration of GnRH neurons ( Cariboni et al, 2011 ).…”

Section: Discussionmentioning

confidence: 67%

FGF8–FGFR1 signaling regulates human GnRH neuron differentiation in a time- and dose-dependent manner

Yellapragada

Eskici

Madhusudan

et al. 2022

Disease Models &Amp; Mechanisms

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Fibroblast growth factor 8 (FGF8), acting through the fibroblast growth factor receptor 1 (FGFR1), has an important role in the development of GnRH neurons. We hypothesized that FGF8 regulates human GnRH neuron differentiation in a time- and dose-dependent manner via FGFR1. Human pluripotent stem cells were differentiated to GnRH neurons with ten days of dual-SMAD inhibition, followed by FGF8 (25 ng/ml, 50 ng/ml or 100 ng/ml for ten days; or 100 ng/ml for two, four, six, and ten days), and Notch inhibition for five days. FGF8 induced expression of GNRH1 in a dose-dependent fashion and the duration of FGF8 exposure correlated positively with GNRH1 expression (P<0.05, Rs=0.49). However, two days of FGF8 (100 ng/ml) induced expression of its target genes such as FOXG1, ETV5, and SPRY2, and continued FGF8 induced dynamic expression of several genes. During FGF8 exposure, FGFR1 localized to the cell surface, and its specific inhibition with PD166866 reduced GNRH1 expression (P<0.05). In neurons, FGFR1 also localized to the nucleus. Our results suggest that dose- and time-dependent FGF8 signaling via FGFR1 is indispensable for human GnRH neuron ontogeny.

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Section: Discussionmentioning

confidence: 67%

FGF8–FGFR1 signaling regulates human GnRH neuron differentiation in a time- and dose-dependent manner

Yellapragada

Eskici

Madhusudan

et al. 2022

Disease Models &Amp; Mechanisms

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“…Reln , Cxcr7 ) (14) or with GD pathogenesis (e.g. Sema3a , Fgfr1 ) (4) emphasizes the efficacy of dissecting the genetic signatures of GnRH neurons in rodents to decipher the molecular mechanisms of GnRH neuron biology and to predict human disease genes.…”

Section: Discussionmentioning

confidence: 99%

“…NLGN3 belongs to the neuroligin family, a class of postsynaptic cell adhesion molecules which regulate synapse organization (10) and dendritic outgrowth (11), and NLGN3 missense variants have been so far associated with autistic spectrum disorder (ASD) (12). Thus, in this work we described two patients carrying novel nonsense NLGN3 variants and presenting with clinical features typical of GD and ASD, therefore providing the first genetic correlation between these two neurodevelopmental disorders, which was previously only implied by a registry-based association study (4).…”

Section: Introductionmentioning

confidence: 86%

“…Disruption in GnRH neuron development or hypothalamic function are the leading causes of genetic reproductive disorders such as Hypogonadotropic Hypogonadism (HH) and Kallmann Syndrome (KS), which are characterized by absent or delayed puberty, due to GnRH deficiency (GD) (3). The known genes causing GD account for only 50% of cases (3, 4), supporting the need for studying the genetic signatures of GnRH neurons as a novel strategy to expedite etiological discovery in the remaining cases. However, the study of the GnRH neuronal system is hampered by the difficulty in obtaining primary GnRH neurons, which are small in number and lack specific markers.…”

Section: Introductionmentioning

confidence: 99%

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Combined omic analyses reveal novel loss-of-function NLGN3 variants in GnRH deficiency and autism

Oleari

Lettieri

Manzini

et al. 2022

Preprint

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Gonadotropin releasing hormone (GnRH) deficiency is a disorder characterized by absent or delayed puberty, with largely unknown genetic causes. The purpose of this study was to obtain and exploit gene expression profiles of GnRH neurons during development to unveil novel biological mechanisms and genetic determinants underlying GnRH deficiency (GD). Here, we combined bioinformatic analyses of primary embryonic and immortalized GnRH neuron transcriptomes with exome sequencing from GD patients to identify candidate causative genes. Among differentially expressed and filtered transcripts, we found loss-of-function (LoF) variants of the autism-linked Neuroligin 3 (NLGN3) gene in two unrelated patients co-presenting with GD and neurodevelopmental traits. We demonstrated that NLGN3 is upregulated in maturing GnRH neurons and that NLGN3 wild type, but not mutant proteins, promotes neuritogenesis when overexpressed in developing GnRH cells. Our data represent proof-of-principle that this complementary approach can identify novel candidate GD genes and demonstrate that LoF NLGN3 variants may contribute to GD. This novel genotype-phenotype correlation implies common genetic mechanisms underlying neurodevelopmental disorders, such as GD and autistic spectrum disorder.

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“…CHH is genetically a heterogeneous disorder with identified X-linked, autosomal dominant, and autosomal recessive patterns of inheritance. With the development of next-generation sequencing (NGS) techniques, pathogenic variants in more than 50 genes have been identified in CHH ( 3 ). However, each gene linked to CHH only seems to underpin a small percentage of total patients, so we are still far from achieving a comprehensive understanding of the genetic basis of CHH.…”

Section: Introductionmentioning

confidence: 99%

The Reproductive Outcome of Women with Hypogonadotropic Hypogonadism in IVF

Zhang

Yang

et al. 2022

Front. Endocrinol.

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ObjectiveThe purpose of this study was to evaluate the reproductive outcome of patients with hypogonadotropic hypogonadism (HH) receiving in vitro fertilization and embryo transfer (IVF-ET).MethodsThe reproductive outcome of 81 HH patients and 112 controls who underwent oocyte retrieval was evaluated retrospectively in the Center for Reproductive Medicine of Peking University Third Hospital from 2010 to 2019.ResultsThe basic levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), androstenedione (A) and prolactin (PRL) were significantly lower in the HH group than the control group. Although the HH patients required a significantly longer stimulation and higher gonadotropin (Gn) doses than the control patients, the total number of oocytes retrieved, fertilized embryos, two pronuclear (2PN) embryos, transferable embryos, fertilization and 2PN rates were comparable between the two groups. Although the live birth rate (LBR) of the first fresh cycle was higher in the control group than the HH group, there was no statistical significance. Then we further divided HH patients into two subgroups according to the etiology. Forty-one cases were termed as congenital HH (CHH), while the other 40 cases were termed as acquired HH (AHH), the latter includes functional hypothalamic amenorrhea (FHA) and pituitary HH (PHH). Our results showed that there were no significant differences in basic clinical characteristics and IVF parameters between the two groups. In the HH group, a total of 119 oocyte retrieval cycles were carried out and they responded adequately to ovulation induction. Urinary human menopausal gonadotropin (HMG) was used alone in 90 cycles while combination of HMG and recombinant human follicle stimulating hormone (rFSH) in the other 29 cycles. There were no significant differences in IVF-related parameters between the two groups. The conservative cumulative live birth rates (CLBRs) after the first, the second and ≥third cycles were 43.21%, 58.02% and 60.49%, respectively, while the corresponding optimal CLBRs were 43.21%, 68.45% and 74.19%. The preterm birth (PTB) rates of singletons and twin pregnancy in HH patients were 8.33% (3/36) and 30.77% (4/13), respectively.ConclusionIVF-ET is an effective treatment for HH patients with infertility and patients can get satisfactory pregnancy outcomes.

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The Differential Roles for Neurodevelopmental and Neuroendocrine Genes in Shaping GnRH Neuron Physiology and Deficiency

Cited by 17 publications

References 242 publications

FGF8–FGFR1 signaling regulates human GnRH neuron differentiation in a time- and dose-dependent manner

FGF8–FGFR1 signaling regulates human GnRH neuron differentiation in a time- and dose-dependent manner

Combined omic analyses reveal novel loss-of-function NLGN3 variants in GnRH deficiency and autism

The Reproductive Outcome of Women with Hypogonadotropic Hypogonadism in IVF

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