# Structure-function analysis of Mullerian Inhibiting Substance (MIS)

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2022 · $389,345

## Abstract

Project Summary: Müllerian Inhibiting Substance (MIS) or Anti- Müllerian Hormone (AMH), originally identified
for its role in male sex differentiation during development, has emerged as a significant molecule in female
reproduction. For example, MIS plays an important role in regulating follicle development and serum levels and
is now used as a measure of ovarian reserve. Mutations in MIS are associated with both male and female
reproductive disorders, including Persistent Müllerian Duct Syndrome (PMDS) in males and Polycystic Ovary
Syndrome (PCOS) in females. As a member of the TGFβ family, MIS signals through a type I and type II receptor.
Uniquely, MIS signals through its own type II receptor MISRII and the type I receptor Alk2, which is utilized by
multiple ligands. While previous studies have detailed TGFβ family ligand interactions, how MIS interacts, at the
molecular level, with MISRII and Alk2 is unknown. The objective of this proposal is to understand how MIS
interacts with its cognate receptors and how specific MIS signaling is generated through these receptors. Here,
we will combine both structural and functional approaches, including X-ray crystallography, cell-based signaling
assays, structure-based engineering, and biological models of fertility and ovarian protection. We will pursue the
following three specific aims (1) determine the crystal structure of MIS with MISRII and Alk2, (2) characterize the
MIS receptors and determine how the generate MIS-specific signaling, using both the extracellular and
intercellular domains and (3) generate MIS analogs that will be tested in both in vitro binding and cell-based
assays, along with in vivo assay including an AAV9 model of follicle suppression. Collectively, this proposal will
uncover how MIS interacts with its receptors providing a platform for developing reagents that modify MIS activity
with the potential for future application in reproductive therapies.

## Key facts

- **NIH application ID:** 10471277
- **Project number:** 5R01HD105818-02
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** THOMAS B THOMPSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $389,345
- **Award type:** 5
- **Project period:** 2021-08-18 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10471277

## Citation

> US National Institutes of Health, RePORTER application 10471277, Structure-function analysis of Mullerian Inhibiting Substance (MIS) (5R01HD105818-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10471277. Licensed CC0.

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