# Role and Regulation of Cellular Polarity in Craniofacial Skeletogenesis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2021 · $485,802

## Abstract

Project Summary
A functional skeletal system depends on the coordinated development of cartilages and bones during
embryogenesis. However, little is known about the cellular and molecular mechanisms that control the
polarized growth of cartilages, which determine endochondral bone size and shape. Unraveling the
signals that direct mesenchymal cells to condense and align into pre-chondrogenic stacks is key to
understanding early events that shape the organization and growth of the skeleton. Elucidating these
processes will allow better diagnosis and treatments for skeletal malformations and birth defects.
Moreover, molecules that control cartilage morphogenesis and differentiation may be of considerable
clinical importance both for improvements in diagnosing and treating congenital birth defects as well as
developing mesenchymal stem cell based therapies for skeletal disorders. Our recent finding that
planar cell polarity pathways are essential for cartilage cells to stack properly, suggests a previously
unappreciated mechanism for patterning cartilage growth plates of long bones as well as growth zones
in bones of the skull. Dramatic results from our laboratory now demonstrate that Hedgehog signaling,
well known for its critical roles in long bone growth plates, also regulates cartilage polarity in zebrafish.
Embryos deficient in Hedgehog signaling show defects in cartilage stacking. Moreover, comparisons of
cartilage growth zones in African cichlid fishes that have evolved dramatically different craniofacial
bone shapes, reveal that growth zone size differences during larval development correlate with these
species-specific shapes. Aim 1 will build upon our previously funded work to address the hypothesis
that Hedgehog signaling regulates growth zone patterning via planar cell polarity. Cartilage phenotypes
will be evaluated in embryos and larvae in which Hedgehog signaling has been manipulated
pharmacologically or genetically. We will identify the polarity pathways regulated by Hedgehog as well
as the signaling and responding cells. Aim 2 will address the functions of polarity in growth zones,
including modes of propagation, responsiveness to Hedgehog, and roles in the perichondrium. For this
we have new transgenics with which we can track polarity, and methods for targeting perichondrial
cells. Finally, Aim 3 will focus on a new “evo-devo” project in the lab, discovering new genes involved in
cartilage polarity and growth zones using quantitative trait locus mapping in cichlids. Together, these
studies will lead to mechanistic insights into the relatively unexplored functions of cellular polarity in
endochondral bones of the vertebrate skeleton. This work will lead to insights into the causes of human
skeletal disorders of Hedgehog signaling, such as brachydactyly, as well as polarity disorders such as
Robinow and Van Maldergem syndromes.

## Key facts

- **NIH application ID:** 10213691
- **Project number:** 5R01DE013828-20
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Thomas F Schilling
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $485,802
- **Award type:** 5
- **Project period:** 2001-04-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10213691

## Citation

> US National Institutes of Health, RePORTER application 10213691, Role and Regulation of Cellular Polarity in Craniofacial Skeletogenesis (5R01DE013828-20). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10213691. Licensed CC0.

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