Ciliary Hedgehog signaling regulates cell survival to build the facial midline

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Abstract

Craniofacial defects are among the most common phenotypes caused by ciliopathies, yet the developmental and molecular etiology of these defects is poorly understood. We investigated multiple mouse models of human ciliopathies (including Tctn2, Cc2d2a and Tmem231 mutants) and discovered that each displays hypotelorism, a narrowing of the midface. As early in development as the end of gastrulation, Tctn2 mutants displayed reduced activation of the Hedgehog (HH) pathway in the prechordal plate, the head organizer. This prechordal plate defect preceded a reduction of HH pathway activation and Shh expression in the adjacent neurectoderm. Concomitant with the reduction of HH pathway activity, Tctn2 mutants exhibited increased cell death in the neurectoderm and facial ectoderm, culminating in a collapse of the facial midline. Enhancing HH signaling by decreasing the gene dosage of a negative regulator of the pathway, Ptch1, decreased cell death and rescued the midface defect in both Tctn2 and Cc2d2a mutants. These results reveal that ciliary HH signaling mediates communication between the prechordal plate and the neurectoderm to provide cellular survival cues essential for development of the facial midline.

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All data generated or analysed during this study are included in the manuscript and supporting files.

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Shaun Abrams

Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-1479-9322
Jeremy F Reiter

Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States

For correspondence
Jeremy.Reiter@ucsf.edu

Competing interests
Jeremy F Reiter, Reviewing editor, eLife.

"This ORCID iD identifies the author of this article:" 0000-0002-6512-320X

Funding

National Institute of Dental and Craniofacial Research (R01DE029454)

Jeremy F Reiter

National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR054396)

Jeremy F Reiter

National Institute of Dental and Craniofacial Research (F30DE024684)

Shaun Abrams

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All mouse protocols were approved by the Institutional Animal Care and Use Committee (IACUC) of the University of California, San Francisco (protocol AN178683).

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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.