# Regulating Establishment of the Mammalian Ovarian Reserve

> **NIH NIH R01** · BROWN UNIVERSITY · 2024 · $418,194

## Abstract

Project Summary
Approximately 12% of couples are infertile and 1% of the female population worldwide experiences primary
ovarian insufficiency (POI) which results from a reduction of the ovarian follicle reserve that often leads to
premature menopause and infertility. Important pathological outcomes associated with early menopause
include osteoporosis, cardiovascular and early cognitive decline. Although several genes have been linked to
women with POI, about 90% of the cases are idiopathic. By uncovering the developmental and molecular
mechanisms underlying the establishment of the initial pool of primordial follicles and the maintenance of the
adult ovarian reserve in the mouse, we will be poised to better understand, diagnose and treat POI in the
future. We have discovered and characterized the roles of a protein called TAF4b that is essential for
establishing the healthy ovarian follicle reserve in the mouse ovary. TAF4b is a gonadal-enriched subunit of the
general transcription factor TFIID, a large multiprotein complex composed of the TATA-box binding protein
(TBP) and 14 TBP-associated factors (TAFs). Our approach to studying the regulation of ovarian follicle
development by TAF4b has elucidated the ovarian functions of TAF4b in the context of a TAF4b-deficient
mouse model. Collectively, these studies have revealed that TAF4b-deficient female mice suffer from
hallmarks of POI including persistent estrous, elevated serum follicle stimulating hormone (FSH) and
accelerated ovarian reserve depletion. In addition to our own work, a number of additional studies have linked
the potential function of human TAF4b in the regulation of fertility in women. Strikingly, the genetic networks
regulated by TAF4b in the mouse ovary appear to be conserved during human fetal oocyte development.
Together, these data implicate the potential deregulation of TAF4b-regulated processes in the context of
human POI and female infertility. Based upon our previous studies, we hypothesize that related TAF4b-
regulated transcriptional events and chromatin modifications in the developing mammalian oocyte serve to
properly establish the initial ovarian reserve and fertility in women. By uncovering the late embryonic oocyte-
specific molecular and developmental functions of TAF4b in transcription, chromatin modification and fetal
oocyte attrition, we aim to identify novel genes, pathways and expression mechanisms in place to ensure the
successful production of high-quality oocytes in women and perhaps one day better diagnose and/or manage
patients with POI and other related deficits of human ovarian health.

## Key facts

- **NIH application ID:** 10990360
- **Project number:** 1R01HD113567-01A1
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Richard Neil Freiman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $418,194
- **Award type:** 1
- **Project period:** 2024-08-16 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10990360

## Citation

> US National Institutes of Health, RePORTER application 10990360, Regulating Establishment of the Mammalian Ovarian Reserve (1R01HD113567-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10990360. Licensed CC0.

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