An Eya1-Notch axis specifies bipotential epibranchial differentiation in mammalian craniofacial morphogenesis

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Abstract

Craniofacial morphogenesis requires proper development of pharyngeal arches and epibranchial placodes. We show that the epibranchial placodes, in addition to giving rise to cranial sensory neurons, generate a novel lineage-related non-neuronal cell population for mouse pharyngeal arch development. Eya1 is essential for the development of epibranchial placodes and proximal pharyngeal arches. We identify an Eya1-Notch regulatory axis that specifies both the neuronal and non-neuronal commitment of the epibranchial placode, where Notch acts downstream of Eya1 and promotes the non-neuronal cell fate. Notch is regulated by the threonine phosphatase activity of Eya1. Eya1 dephosphorylates p-threonine-2122 of the Notch1 intracellular domain (Notch1 ICD), which increases the stability of Notch1 ICD and maintains Notch signaling activity in the non-neuronal epibranchial placodal cells. Our data unveil a more complex differentiation program in epibranchial placodes and an important role for the Eya1-Notch axis in craniofacial morphogenesis.

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Haoran Zhang

School of Biomedical Sciences, The University of Hong Kong, Hong Kong, Hong Kong

Competing interests
The authors declare that no competing interests exist.
Li Wang

School of Biomedical Sciences, The University of Hong Kong, Hong Kong, Hong Kong

Competing interests
The authors declare that no competing interests exist.
Elaine Yee Man Wong

School of Biomedical Sciences, The University of Hong Kong, Hong Kong, Hong Kong

Competing interests
The authors declare that no competing interests exist.
Sze Lan Tsang

School of Biomedical Sciences, The University of Hong Kong, Hong Kong, Hong Kong

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The authors declare that no competing interests exist.
Pin-Xian Xu

Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, United States

Competing interests
The authors declare that no competing interests exist.
Urban Lendahl

Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden

Competing interests
The authors declare that no competing interests exist.
Mai Har Sham

School of Biomedical Sciences, The University of Hong Kong, Hong Kong, Hong Kong

For correspondence
mhsham@hku.hk

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-1179-7839

Funding

Research Grants Council, University Grants Committee (RGC GRF 777411)

Mai Har Sham

Research Grants Council, University Grants Committee (RGC GRF 17113415)

Mai Har Sham

Cancerfonden (SCS X2017-2019,335)

Urban Lendahl

Vetenskapsrådet (project grant 2014-2018,RX331)

Urban Lendahl

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All mouse experiments were performed in strict accordance with the recommendations and approved by the University of Hong Kong animal research ethics committee (CULATR No. 3329-14 and 3862-15).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.