# Iroquois function in the female reproductive tract

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $662,206

## Abstract

Project summary/Abstract
Two existential threats to female fertility include the premature loss of the ovarian reserve and early
implantation/placentation failure. We recently discovered that Irx3 and Irx5, two of six members of the
Iroquois homeobox (Irx) transcription factor family, show remarkable conservation of molecular and
cellular actions associated with cognate cell-cell transitions critical for germline nest breakdown and
primordial follicle formation (ovarian reserve) during ovary development and embryo-endometrial
interactions leading to vasculogenesis during implantation and establishment of pregnancy. Previously,
we employed a series of Irx3/5 mutant mouse models, including an Sf1-Cre/Flox strategy to highlight
autonomous roles for Irx3 vs Irx5, especially in somatic cells. The fertility profiles for these mice also
indicated that developmental expression of Irx3 contributes to the adult follicle’s response to external
growth and ovulation signals and suggested that Irx3 has a critical role in oocyte integrity. AIM 1 is
designed to discover the roles for Irx3 in the oocyte and uncover downstream targets and regulation
profiles over time in ovary development. Ovarian histology and follicle counts identified oocyte deficits,
but reproductive data suggested that other factors were also contributing to the subfertility phenotype in
Irx3 knockout mice (Irx3 KO). Indeed, ablation of Irx3 in female mice resulted in a subfertile phenotype
with fewer pups born in each litter. Our studies indicated a marked induction of Irx3 at the onset of
decidualization and we observed a progressive loss of embryos starting at the decidual phase and
extending through the end of pregnancy indicating a disrupted uterine response to the embryo that
caused deficits in placentation. AIM 2 will test the hypothesis that Irx3 integrates stromal-endothelium
and stromal-trophoblast interactions to ensure successful establishment of pregnancy. Finally, we
observed punctate staining for IRX3 within cytoplasm of oocytes and uterine decidual cells. Based on our
observations that IRX3 plays an important role in mediating cell-cell interactions, AIM 3 is designed to
examine cytoplasmic signaling and localization of cytoskeletal machinery with respect to IRX3 presence.
Altogether, our studies are designed to discover how Iroquois homeobox proteins mediate germline nest
breakdown and primordial follicle formation to establish responsive follicles with healthy oocytes and
decidualization that promotes a successful implantation and placentation program. Successful outcomes
will increase our understanding of the biology that results in a healthy ovarian reserve and optimal
uterine conditions for early embryo survival.

## Key facts

- **NIH application ID:** 10521759
- **Project number:** 1R01HD107846-01A1
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Indrani C Bagchi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $662,206
- **Award type:** 1
- **Project period:** 2022-09-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10521759

## Citation

> US National Institutes of Health, RePORTER application 10521759, Iroquois function in the female reproductive tract (1R01HD107846-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10521759. Licensed CC0.

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