# GnRH Receptor Signaling Specificity

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $700,345

## Abstract

Reproduction depends on the orchestration of LH and FSH biosynthesis and release by neuroendocrine,
endocrine, autocrine and paracrine stimuli. Mouse studies show that both GnRH and activin/TGFβ signaling
are needed for Fshβ, which is required in the mouse for female reproduction. Thus reproduction depends on a
GnRH/activin “AND” logic gate having an unknown molecular basis. Relevant to this problem, our recent
studies support a new working model for gene regulation in the gonadotrope. Using single cell (sc) RNA
quantification we find that gene induction to different GnRH concentrations is all-or-none, with genes showing a
characteristic increased probability of turning on in single cells at higher concentrations of GnRH . Thus what
we consider transcriptional regulation can be modeled as probabilistically activated binary on-off switches at
the sc level. Differences in regulatory mechanisms detected at sc resolution and evidence for gonadotrope
subtypes indicate the importance of sc transcriptome and epigenetic assays in extending these studies to
gonadotrope regulation in vivo. Based on a probabilistic gene control model, recent findings and review of the
literature, we hypothesize that the GnRH/activin Fshβ gate results from relative effects of activin and GnRH
signaling on the immediate probability of Fshβ gene activation and on the promoter accessibility state, most
likely by activin signaling predominantly increasing Fshβ gene accessibility and GnRH increasing the
immediate probability of activation. Accordingly, we propose in Aim 1 to study the separate and combination
effects of activin and GnRH and to test the probabilistic all-or-none (quantal) model in LβT2 cells using bulk
ATAC-seq chromatin accessibility assays and sc integrated fluidics circuit mRNA assays. In Aim 2, we will
characterize the relationship of chromatin landscape and gene expression in male mice and in female mice
and identify gonadotrope subtypes and their regulatory processes through the estrous cycle using sc RNA-seq
and sc ATAC-seq assays. In Aim 3 we will use sc RNA-seq and sc ATAC-seq to study mechanisms
responsible for the Fshβ gate using GnRH and activin-signaling deficient mouse models. These studies will be
interpreted using state-of-the-art bionformatic frameworks and, when necessary, by modifying or developing
new methods. While these studies are designed to test specific hypotheses, the use of genome-wide discovery
platforms will provide data for mining and new hypothesis generation, such as understanding diverse
autocrine/paracrine regulatory mechanisms and will generate a resource for the field. The proposed research
program should provide fundamental insight into the molecular identity, heterogeneity and regulation of
gonadotropes and an improved understanding of the mechanisms for the gonadotrope gene control
mechanisms that underlie reproduction.

## Key facts

- **NIH application ID:** 10463727
- **Project number:** 5R01DK046943-26
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** STUART C. SEALFON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $700,345
- **Award type:** 5
- **Project period:** 1993-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463727

## Citation

> US National Institutes of Health, RePORTER application 10463727, GnRH Receptor Signaling Specificity (5R01DK046943-26). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10463727. Licensed CC0.

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