# A protein traffic control system that regulates left-right patterning and heart development

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $756,685

## Abstract

Project Summary
A protein traffic control system that regulates left-right patterning and heart development
Structural birth defects represent the leading cause of infant deaths. Congenital Heart Defects (CHDs) are the
most common structural birth defects, affecting ~40,000 babies each year. Amongst CHDs, a disproportionate
burden of mortality and morbidity is due to “severe” CHDs, defined as those that require surgery or a
procedure before the first year of life. The molecular mechanisms that drive severe CHDs are incompletely
understood, hampering preventative, diagnostic and therapeutic advances. Data from mouse studies and
human birth registries have revealed a striking association between severe CHDs and heterotaxy, defects in
left-right patterning of visceral organs. By integrating the expertise of three investigators in signal transduction,
mouse development, human genetics and CHDs, we have identified a novel cell-surface ubiquitination
pathway (the “MMM pathway”) that plays widespread roles in the patterning of tissues during development.
Disruption of this pathway leads to a characteristic syndrome of heterotaxy with severe CHDs in embryonic
mice, along with defects in other tissues such as the limb, skeleton and face. Three dimensional
reconstructions of the intracardiac anatomy of MMM mutant embryos reveal the presence of severe CHDs also
often seen in human patients, including double outlet right ventricle and transposition of the great arteries. The
MMM pathway is anchored at the cell surface by a receptor-like ubiquitin ligase complex composed of MEGF8,
a single-pass transmembrane protein, and MGRN1, a RING superfamily E3 ligase. This unique
membrane-tethered ubiquitination machine attenuates signaling through the iconic Hedgehog (Hh) pathway.
Mechanistically, the MMM components decrease the abundance of the Hh transducer Smoothened (SMO) by
direct ubiquitination, thereby reducing the sensitivity of target cells to Hh ligands. We propose to test the
hypothesis that the MMM pathway functions as a traffic control system for signaling receptors that regulate
left-right patterning and cardiac development. Our first aim is focused on understanding the biochemical
function and developmental roles of MOSMO, an uncharacterized tetraspan membrane protein that we
identified as a third component of the MMM pathway. In the second aim, we test whether the heterotaxy and
CHDs seen in MMM mutant embryos are caused by elevated Hh signaling strength at critical periods in
development and also search for other signaling receptors regulated by the MMM pathway. Finally, we
leverage our comprehensive biochemical and developmental assays for MMM proteins to test the functionality
of rare coding variants in MMM genes seen in human patients with severe CHDs. Successful completion of this
project will uncover trafficking and signaling mechanisms that underlie the long-observed link between left-right
patterning and heart development and consequently advanc...

## Key facts

- **NIH application ID:** 10181808
- **Project number:** 1R01HL157103-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Teresa M Gunn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $756,685
- **Award type:** 1
- **Project period:** 2021-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10181808

## Citation

> US National Institutes of Health, RePORTER application 10181808, A protein traffic control system that regulates left-right patterning and heart development (1R01HL157103-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10181808. Licensed CC0.

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