# Mechanisms of Eph/Ephrin signaling in craniofacial morphogenesis and craniofrontonasal syndrome

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $603,207

## Abstract

Project summary
Congenital anomalies affect 1% of live births, with one-third of these displaying craniofacial abnormalities.
Great advances have been made in our understanding of the genetic causes of many of these conditions, but
lack of understanding of the underlying developmental, cellular, and molecular mechanisms continues to
stymie personalized medicine approaches to treat these conditions. Craniofrontonasal syndrome (CFNS) is an
X-linked condition caused by mutations in the EFNB1 gene that affects craniofacial and thoracic skeleton, and
neurological development. Complete loss of EFNB1 function results in hypertelorism and cleft palate, but
mosaic loss of EFNB1 in only some cells, has more severe consequences, resulting also in midfacial
hypoplasia, coronal craniosynostosis, limb abnormalities, and agenesis of the corpus callosum. Mouse Efnb1
mutants effectively model CFNS, exhibiting most of the same phenotypes. Efnb1 encodes Ephrin-B1 a
transmembrane signaling molecule that binds to EphB receptor tyrosine kinases to regulate cell position. In
Efnb1+/- heterozygous females, X chromosome inactivation leads to mosaicism for Ephrin-B1 function and
subsequent sorting-out of Ephrin-B1-expressing cells from Ephrin-B1 mutant cells. This self-organizing
capacity is a general feature of Eph/Ephrin signaling in many different tissues. In craniofacial development, we
hypothesize that Ephrin-B1 plays a critical role in the organization of the craniofacial mesenchyme, though how
this occurs, and how it affects craniofacial shape, remains unknown. It is therefore our goal to understand how
Ephrin-B1 regulates normal craniofacial morphogenesis at the developmental, cellular and molecular scales.
First, to understand how Ephrin-B1 regulates changes in shape of specific craniofacial embryonic primordia,
we will utilize micro-computed tomography scanning to perform landmark-based morphometric analysis of
mouse embryos lacking Ephrin-B1 in specific structures. Using a similar approach, we will evaluate the relative
involvement of three receptors EphB1, EphB2 and EphB3 in craniofacial morphogenesis. Second, we will
utilize new tools to study the distribution, shape, density, and polarity of the craniofacial mesenchyme in normal
and Efnb1 mutant embryos. Finally, we will harness CRISPR genome editing technology to perform a
functional screen of candidate genes to identify the signaling pathways downstream of Ephrin-B1/EphB
signaling. This work will provide new insights into the mechanisms by which Ephrin-B1 normally controls
mesenchymal cell behaviors in craniofacial morphogenesis, and determine how its loss results in pathological
changes in craniofacial shape. These studies will therefore provide foundational knowledge toward our long-
term goal of developing improved therapies for the treatment of individuals with craniofacial anomalies and an
improved understanding of the fundamental processes of craniofacial morphogenesis. The underlying cellular
and mo...

## Key facts

- **NIH application ID:** 9933882
- **Project number:** 5R01DE023337-08
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Jeffrey Ohmann Bush
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $603,207
- **Award type:** 5
- **Project period:** 2013-07-09 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933882

## Citation

> US National Institutes of Health, RePORTER application 9933882, Mechanisms of Eph/Ephrin signaling in craniofacial morphogenesis and craniofrontonasal syndrome (5R01DE023337-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9933882. Licensed CC0.

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