# Novel regulation of early follicle formation

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $324,063

## Abstract

The fundamental mechanism responsible for the transition of undifferentiated somatic cells (SCs) into gran-
ulosa cells (GCs) during primordial follicle (PF) formation is poorly understood. Women with premature ovarian
failure (POF), Turner Syndrome or inactivating mutation of FSH receptor are infertile and have defective and
non-growing PFs. Therefore, the basic research on PF formation is necessary to understand the molecular basis
of normal and defective folliculogenesis. We present compelling evidence that (1) bone morphogenic protein 2
(BMP2, a SC-derived ligand), GDF9 (an oocyte-derived ligand) and estradiol-17 (E2, an ovarian hormone) inter-
act to promote PF formation in fetal ovaries, (2) the paracrine actions of GDF9 require BMP2 priming of SCs,
and (3) inactivation of cadherin 2 (CDH2) interferes with PF formation.19 These important findings lead us to
hypothesize that BMP2 and GDF9 spatio-temporally promote the transition of SCs into GCs and their
assembly with the oocytes. E2 modulates the actions of BMP2 by upregulating the synthesis of BMP2
ligand and receptors. The specific aims (Fig. 1) are (1) Determine the mechanism of BMP2-mediated pri-
mordial follicle (PF) formation. The objectives are, (1) To determine if BMP2 regulates the transition of SCs
into GCs, (2) To determine if GDF9 action is required for or facilitates the transition of SCs to GCs, and (3) To
determine if GDF9 facilitates oocyte-granulosa cell adhesion and assembly. We will knockdown BMP2 or GDF9
expression or block their actions or alter ALK2/3 activities in E15 hamster ovaries in vitro by small molecule
inhibitors or shRNA. (2) Determine if estradiol-17 (E2) regulates BMP2-ALK3/ ALK2 system. The objective
is to determine if E2 affects PF formation by regulating the expression and action of BMP2. We will knockdown
or block BMP2 action or alter ALK2/3 activities by small molecule inhibitors or shRNA in hamster fetal ovaries,
and in ovary recombinants to determine the mechanism of E2-induced SC to GC transition. (3) Analysis of gene
networks affected by BMP2 or GDF9 during PF formation. The objective is to identify and analyze gene
networks and corresponding pathways in SCs that are targeted by BMP2 or GDF9 during PF formation. We will
use RNAseq analysis to determine differentially expressed genes (DEGs) in SCs of ovaries exposed to BMP2
or GDF9. High stringency cut off along with bioinformatics analysis will be used to select candidate genes for
biological validation and will be prioritized based on their role in mesenchymal-epithelial transition (MET), in
follicular development and functions, and the probability of their defects causing ovarian dysfunction. Biological
validation will be accomplished using approaches outlined in Aim 1. This study will provide novel information to
understand the basic mechanism responsible for the transition of undifferentiated SCs into GCs during PF for-
mation, and may shed light to better understand the molecular basis of defe...

## Key facts

- **NIH application ID:** 9952398
- **Project number:** 5R01HD093887-02
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** SHYAMAL K. ROY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $324,063
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952398

## Citation

> US National Institutes of Health, RePORTER application 9952398, Novel regulation of early follicle formation (5R01HD093887-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9952398. Licensed CC0.

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