Primary cilia deficiency in neural crest cells models anterior segment dysgenesis in mouse

Céline Portal; Panteleimon Rompolas; Peter Lwigale; Carlo Iomini

doi:10.7554/eLife.52423

Primary cilia deficiency in neural crest cells models anterior segment dysgenesis in mouse

Céline Portal, Panteleimon Rompolas, Peter Lwigale, Carlo Iomini

School of Medicine

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Defects affecting tissues of the anterior segment (AS) of the eye lead to a group of highly debilitating disorders called Anterior Segment Dysgenesis (ASD). Despite the identification of some causative genes, the pathogenesis of ASD remains unclear. Interestingly, several ciliopathies display conditions of the AS. Using conditional targeting of Ift88 with Wnt1-Cre, we show that primary cilia of neural crest cells (NCC), precursors of most AS structures, are indispensable for normal AS development and their ablation leads to ASD conditions including abnormal corneal dimensions, defective iridocorneal angle, reduced anterior chamber volume and corneal neovascularization. Mechanistically, NCC cilia ablation abolishes hedgehog (Hh) signaling in the periocular mesenchyme (POM) canonically activated by choroid-secreted Indian Hh, reduces proliferation of POM cells surrounding the retinal pigment epithelium and decreases the expression of Foxc1 and Pitx2, two transcription factors identified as major ASD causative genes. Thus, we uncovered a signaling axis linking cilia and ASD.

Original language	English (US)
Article number	e52423
Journal	eLife
Volume	8
DOIs	https://doi.org/10.7554/eLife.52423
State	Published - Dec 2019

Keywords

Cornea
Eye disease
Hedgehog signaling
Neural crest
Primary cilia

ASJC Scopus subject areas

General Neuroscience
General Immunology and Microbiology
General Biochemistry, Genetics and Molecular Biology

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10.7554/eLife.52423

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@article{b72e003928fd407592079a4509d61f9c,

title = "Primary cilia deficiency in neural crest cells models anterior segment dysgenesis in mouse",

abstract = "Defects affecting tissues of the anterior segment (AS) of the eye lead to a group of highly debilitating disorders called Anterior Segment Dysgenesis (ASD). Despite the identification of some causative genes, the pathogenesis of ASD remains unclear. Interestingly, several ciliopathies display conditions of the AS. Using conditional targeting of Ift88 with Wnt1-Cre, we show that primary cilia of neural crest cells (NCC), precursors of most AS structures, are indispensable for normal AS development and their ablation leads to ASD conditions including abnormal corneal dimensions, defective iridocorneal angle, reduced anterior chamber volume and corneal neovascularization. Mechanistically, NCC cilia ablation abolishes hedgehog (Hh) signaling in the periocular mesenchyme (POM) canonically activated by choroid-secreted Indian Hh, reduces proliferation of POM cells surrounding the retinal pigment epithelium and decreases the expression of Foxc1 and Pitx2, two transcription factors identified as major ASD causative genes. Thus, we uncovered a signaling axis linking cilia and ASD.",

keywords = "Cornea, Eye disease, Hedgehog signaling, Neural crest, Primary cilia",

author = "C{\'e}line Portal and Panteleimon Rompolas and Peter Lwigale and Carlo Iomini",

note = "Funding Information: of Health grants EY022639 to C.I., EY022158 to P.Y.L., EY030599 to P.R., EY001765 core grant Funding Information: We thank L. Grisanti and Q. Liu for their involvement during the early stages of this project, members of the Mlodzik and Iomini labs as well as members of the Wilmer Cornea Group for helpful inputs and discussions. We thank Nada Marjanovic and Pei-Yu Kuo for their help with qPCR and cell sorting experiments. We are particularly grateful to Rebecca Sherburn and James Foster for critical comments to the manuscript. This work was supported by the National Institutes of Health grants EY022639 to C.I., EY022158 to P.Y.L., EY030599 to P.R., EY001765 core grant to the Wilmer Eye Institute, the RPB Unrestricted Grant (Wilmer), the Research to Prevent Blindness Dolly Green Special Scholar Award to C.I., and the Wilmer Eye Institute Seed Fund to C.I. Funding Information: Foster for critical comments to the manuscript. This work was supported by the National Institutes Publisher Copyright: {\textcopyright} 2019, eLife Sciences Publications Ltd. All rights reserved.",

year = "2019",

month = dec,

doi = "10.7554/eLife.52423",

language = "English (US)",

volume = "8",

journal = "eLife",

issn = "2050-084X",

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T1 - Primary cilia deficiency in neural crest cells models anterior segment dysgenesis in mouse

AU - Portal, Céline

AU - Rompolas, Panteleimon

AU - Lwigale, Peter

AU - Iomini, Carlo

N1 - Funding Information: of Health grants EY022639 to C.I., EY022158 to P.Y.L., EY030599 to P.R., EY001765 core grant Funding Information: We thank L. Grisanti and Q. Liu for their involvement during the early stages of this project, members of the Mlodzik and Iomini labs as well as members of the Wilmer Cornea Group for helpful inputs and discussions. We thank Nada Marjanovic and Pei-Yu Kuo for their help with qPCR and cell sorting experiments. We are particularly grateful to Rebecca Sherburn and James Foster for critical comments to the manuscript. This work was supported by the National Institutes of Health grants EY022639 to C.I., EY022158 to P.Y.L., EY030599 to P.R., EY001765 core grant to the Wilmer Eye Institute, the RPB Unrestricted Grant (Wilmer), the Research to Prevent Blindness Dolly Green Special Scholar Award to C.I., and the Wilmer Eye Institute Seed Fund to C.I. Funding Information: Foster for critical comments to the manuscript. This work was supported by the National Institutes Publisher Copyright: © 2019, eLife Sciences Publications Ltd. All rights reserved.

PY - 2019/12

Y1 - 2019/12

N2 - Defects affecting tissues of the anterior segment (AS) of the eye lead to a group of highly debilitating disorders called Anterior Segment Dysgenesis (ASD). Despite the identification of some causative genes, the pathogenesis of ASD remains unclear. Interestingly, several ciliopathies display conditions of the AS. Using conditional targeting of Ift88 with Wnt1-Cre, we show that primary cilia of neural crest cells (NCC), precursors of most AS structures, are indispensable for normal AS development and their ablation leads to ASD conditions including abnormal corneal dimensions, defective iridocorneal angle, reduced anterior chamber volume and corneal neovascularization. Mechanistically, NCC cilia ablation abolishes hedgehog (Hh) signaling in the periocular mesenchyme (POM) canonically activated by choroid-secreted Indian Hh, reduces proliferation of POM cells surrounding the retinal pigment epithelium and decreases the expression of Foxc1 and Pitx2, two transcription factors identified as major ASD causative genes. Thus, we uncovered a signaling axis linking cilia and ASD.

AB - Defects affecting tissues of the anterior segment (AS) of the eye lead to a group of highly debilitating disorders called Anterior Segment Dysgenesis (ASD). Despite the identification of some causative genes, the pathogenesis of ASD remains unclear. Interestingly, several ciliopathies display conditions of the AS. Using conditional targeting of Ift88 with Wnt1-Cre, we show that primary cilia of neural crest cells (NCC), precursors of most AS structures, are indispensable for normal AS development and their ablation leads to ASD conditions including abnormal corneal dimensions, defective iridocorneal angle, reduced anterior chamber volume and corneal neovascularization. Mechanistically, NCC cilia ablation abolishes hedgehog (Hh) signaling in the periocular mesenchyme (POM) canonically activated by choroid-secreted Indian Hh, reduces proliferation of POM cells surrounding the retinal pigment epithelium and decreases the expression of Foxc1 and Pitx2, two transcription factors identified as major ASD causative genes. Thus, we uncovered a signaling axis linking cilia and ASD.

KW - Cornea

KW - Eye disease

KW - Hedgehog signaling

KW - Neural crest

KW - Primary cilia

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SN - 2050-084X

VL - 8

JO - eLife

JF - eLife

M1 - e52423

ER -

Primary cilia deficiency in neural crest cells models anterior segment dysgenesis in mouse

Abstract

Keywords

ASJC Scopus subject areas

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