Ciliary Hedgehog signaling regulates cell survival to build the facial midline

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 di...

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Autores principales:	Shaun R Abrams, Jeremy F Reiter
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	primary cilia Hedgehog signaling ciliopathy dependence receptor apoptosis craniofacial development Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/f11836e51aab41898f41c1a9efe6035c
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spelling	oai:doaj.org-article:f11836e51aab41898f41c1a9efe6035c2021-11-15T09:08:17ZCiliary Hedgehog signaling regulates cell survival to build the facial midline10.7554/eLife.685582050-084Xe68558https://doaj.org/article/f11836e51aab41898f41c1a9efe6035c2021-10-01T00:00:00Zhttps://elifesciences.org/articles/68558https://doaj.org/toc/2050-084XCraniofacial 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.Shaun R AbramsJeremy F ReitereLife Sciences Publications Ltdarticleprimary ciliaHedgehog signalingciliopathydependence receptorapoptosiscraniofacial developmentMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	primary cilia Hedgehog signaling ciliopathy dependence receptor apoptosis craniofacial development Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	primary cilia Hedgehog signaling ciliopathy dependence receptor apoptosis craniofacial development Medicine R Science Q Biology (General) QH301-705.5 Shaun R Abrams Jeremy F Reiter Ciliary Hedgehog signaling regulates cell survival to build the facial midline
description	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.
format	article
author	Shaun R Abrams Jeremy F Reiter
author_facet	Shaun R Abrams Jeremy F Reiter
author_sort	Shaun R Abrams
title	Ciliary Hedgehog signaling regulates cell survival to build the facial midline
title_short	Ciliary Hedgehog signaling regulates cell survival to build the facial midline
title_full	Ciliary Hedgehog signaling regulates cell survival to build the facial midline
title_fullStr	Ciliary Hedgehog signaling regulates cell survival to build the facial midline
title_full_unstemmed	Ciliary Hedgehog signaling regulates cell survival to build the facial midline
title_sort	ciliary hedgehog signaling regulates cell survival to build the facial midline
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/f11836e51aab41898f41c1a9efe6035c
work_keys_str_mv	AT shaunrabrams ciliaryhedgehogsignalingregulatescellsurvivaltobuildthefacialmidline AT jeremyfreiter ciliaryhedgehogsignalingregulatescellsurvivaltobuildthefacialmidline
_version_	1718428529502191616

Ciliary Hedgehog signaling regulates cell survival to build the facial midline

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