# Molecular mechanisms that regulate target cell sensitivity to Hedgehog morphogens

> **NIH NIH K99** · STANFORD UNIVERSITY · 2020 · $99,876

## Abstract

PROJECT SUMMARY/ABSTRACT
Hedgehog (Hh) signaling is essential for tissue patterning and cell proliferation in development, regeneration,
and disease. As classical morphogens, Hh ligands direct cell fate decisions in a manner dependent on
signaling strength. Precise regulation of signaling strength is critical for proper tissue development and
maintenance, highlighted by the fact that even modest changes in the signaling amplitude can result in human
birth defects. While a large body of work has shown that signaling strength is influenced by the concentration
and exposure time of Hh ligands, an equally important layer of regulation remains unrecognized and unstudied:
How is the sensitivity of target cells to morphogens regulated? During the first phase of my postdoctoral
training, I used genome-wide CRISPR screens to discover three genes that function to attenuate Hh signaling
in target cells: Mosmo, Megf8, and Mgrn1 (the “MMM module”). Disruption of the MMM module in both
fibroblasts and neural progenitor cells (NPCs) resulted in a ~10-fold increase in sensitivity to Hh ligands and
altered neural cell-fate decisions, driven by a marked increase in levels of the transmembrane transducer
Smoothened (SMO) at primary cilia. These studies lead to the hypothesis that the MMM module regulates
signaling strength in target cells by regulating the sub-cellular localization of Hh pathway components. To test
this hypothesis, I will (1) determine the mechanism by which the MMM module regulates SMO trafficking, (2)
illuminate the role of ubiquitination in MMM-regulated SMO trafficking and Hh sensitivity, and (3) identify the
function of the MMM module during embryonic development. These studies will unravel the molecular basis
and physiological function of a novel mechanism that allows target cells to modify their responses to
extracellular cues and consequently suggest new strategies to modulate Hh signaling strength in disease
states. In graduate school, I trained as a mouse geneticist and embryologist. During the first phase of my
postdoc, I learned how to use CRISPR technology to conduct genome-wide loss-of-function screens and to
test the function of specific genes in sophisticated in vitro differentiation assays. Support from the K99
program, the resources available at Stanford University, and the expertise of my advisory panel will allow me to
develop critical new skills in the areas of advanced microscopy, protein biochemistry, and mass spectrometry
to understand the biochemical and biological function of developmental regulators like the MMM module. I will
accomplish this with training from my mentor Dr. Rajat Rohatgi (biochemistry and cancer biology), my co-
mentor Dr. Tim Stearns (cilia biology), and a strong advisory panel composed of members with expertise in
protein trafficking, computational biology, developmental biology, and mass spectrometry. The training and
mentorship I receive during my K99/R00 award will provide a critical stepping stone ...

## Key facts

- **NIH application ID:** 9926295
- **Project number:** 5K99GM132518-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Jennifer Kong
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $99,876
- **Award type:** 5
- **Project period:** 2019-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926295

## Citation

> US National Institutes of Health, RePORTER application 9926295, Molecular mechanisms that regulate target cell sensitivity to Hedgehog morphogens (5K99GM132518-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9926295. Licensed CC0.

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