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Porcn is essential for growth and invagination of the mammalian optic cup
Microphthalmia, anophthalmia, and coloboma (MAC) are congenital ocular malformations causing 25% of childhood blindness. The X-linked disorder Focal Dermal Hypoplasia (FDH) is frequently associated with MAC and results from mutations in Porcn, a membrane bound O-acyl transferase required for palmito...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9661423/ https://www.ncbi.nlm.nih.gov/pubmed/36393832 http://dx.doi.org/10.3389/fcell.2022.1016182 |
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author | Fuhrmann, Sabine Ramirez, Sara Mina Abouda, Mirna Campbell, Clorissa D. |
author_facet | Fuhrmann, Sabine Ramirez, Sara Mina Abouda, Mirna Campbell, Clorissa D. |
author_sort | Fuhrmann, Sabine |
collection | PubMed |
description | Microphthalmia, anophthalmia, and coloboma (MAC) are congenital ocular malformations causing 25% of childhood blindness. The X-linked disorder Focal Dermal Hypoplasia (FDH) is frequently associated with MAC and results from mutations in Porcn, a membrane bound O-acyl transferase required for palmitoylation of Wnts to activate multiple Wnt-dependent pathways. Wnt/β-catenin signaling is suppressed in the anterior neural plate for initiation of eye formation and is subsequently required during differentiation of the retinal pigment epithelium (RPE). Non-canonical Wnts are critical for early eye formation in frog and zebrafish. However, it is unclear whether this also applies to mammals. We performed ubiquitous conditional inactivation of Porcn in mouse around the eye field stage. In Porcn ( CKO ), optic vesicles (OV) arrest in growth and fail to form an optic cup. Ventral proliferation is significantly decreased in the mutant OV, with a concomitant increase in apoptotic cell death. While pan-ocular transcription factors such as PAX6, SIX3, LHX2, and PAX2 are present, indicative of maintenance of OV identity, regional expression of VSX2, MITF, OTX2, and NR2F2 is downregulated. Failure of RPE differentiation in Porcn ( CKO ) is consistent with downregulation of the Wnt/β-catenin effector LEF1, starting around 2.5 days after inactivation. This suggests that Porcn inactivation affects signaling later than a potential requirement for Wnts to promote eye field formation. Altogether, our data shows a novel requirement for Porcn in regulating growth and morphogenesis of the OV, likely by controlling proliferation and survival. In FDH patients with ocular manifestations, growth deficiency during early ocular morphogenesis may be the underlying cause for microphthalmia. |
format | Online Article Text |
id | pubmed-9661423 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-96614232022-11-15 Porcn is essential for growth and invagination of the mammalian optic cup Fuhrmann, Sabine Ramirez, Sara Mina Abouda, Mirna Campbell, Clorissa D. Front Cell Dev Biol Cell and Developmental Biology Microphthalmia, anophthalmia, and coloboma (MAC) are congenital ocular malformations causing 25% of childhood blindness. The X-linked disorder Focal Dermal Hypoplasia (FDH) is frequently associated with MAC and results from mutations in Porcn, a membrane bound O-acyl transferase required for palmitoylation of Wnts to activate multiple Wnt-dependent pathways. Wnt/β-catenin signaling is suppressed in the anterior neural plate for initiation of eye formation and is subsequently required during differentiation of the retinal pigment epithelium (RPE). Non-canonical Wnts are critical for early eye formation in frog and zebrafish. However, it is unclear whether this also applies to mammals. We performed ubiquitous conditional inactivation of Porcn in mouse around the eye field stage. In Porcn ( CKO ), optic vesicles (OV) arrest in growth and fail to form an optic cup. Ventral proliferation is significantly decreased in the mutant OV, with a concomitant increase in apoptotic cell death. While pan-ocular transcription factors such as PAX6, SIX3, LHX2, and PAX2 are present, indicative of maintenance of OV identity, regional expression of VSX2, MITF, OTX2, and NR2F2 is downregulated. Failure of RPE differentiation in Porcn ( CKO ) is consistent with downregulation of the Wnt/β-catenin effector LEF1, starting around 2.5 days after inactivation. This suggests that Porcn inactivation affects signaling later than a potential requirement for Wnts to promote eye field formation. Altogether, our data shows a novel requirement for Porcn in regulating growth and morphogenesis of the OV, likely by controlling proliferation and survival. In FDH patients with ocular manifestations, growth deficiency during early ocular morphogenesis may be the underlying cause for microphthalmia. Frontiers Media S.A. 2022-10-31 /pmc/articles/PMC9661423/ /pubmed/36393832 http://dx.doi.org/10.3389/fcell.2022.1016182 Text en Copyright © 2022 Fuhrmann, Ramirez, Mina Abouda and Campbell. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Cell and Developmental Biology Fuhrmann, Sabine Ramirez, Sara Mina Abouda, Mirna Campbell, Clorissa D. Porcn is essential for growth and invagination of the mammalian optic cup |
title | Porcn is essential for growth and invagination of the mammalian optic cup |
title_full | Porcn is essential for growth and invagination of the mammalian optic cup |
title_fullStr | Porcn is essential for growth and invagination of the mammalian optic cup |
title_full_unstemmed | Porcn is essential for growth and invagination of the mammalian optic cup |
title_short | Porcn is essential for growth and invagination of the mammalian optic cup |
title_sort | porcn is essential for growth and invagination of the mammalian optic cup |
topic | Cell and Developmental Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9661423/ https://www.ncbi.nlm.nih.gov/pubmed/36393832 http://dx.doi.org/10.3389/fcell.2022.1016182 |
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