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Common basis for orofacial clefting and cortical interneuronopathy
Orofacial clefts (OFCs) of the lip and/or palate are among the most common human birth defects. Current treatment strategies focus on functional and cosmetic repair but even when this care is available, individuals born with OFCs are at high risk for persistent neurobehavioral problems. In addition...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5802454/ https://www.ncbi.nlm.nih.gov/pubmed/29317601 http://dx.doi.org/10.1038/s41398-017-0057-7 |
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author | Ansen-Wilson, Lydia J. Everson, Joshua L. Fink, Dustin M. Kietzman, Henry W. Sullivan, Ruth Lipinski, Robert J. |
author_facet | Ansen-Wilson, Lydia J. Everson, Joshua L. Fink, Dustin M. Kietzman, Henry W. Sullivan, Ruth Lipinski, Robert J. |
author_sort | Ansen-Wilson, Lydia J. |
collection | PubMed |
description | Orofacial clefts (OFCs) of the lip and/or palate are among the most common human birth defects. Current treatment strategies focus on functional and cosmetic repair but even when this care is available, individuals born with OFCs are at high risk for persistent neurobehavioral problems. In addition to learning disabilities and reduced academic achievement, recent evidence associates OFCs with elevated risk for a constellation of psychiatric outcomes including anxiety disorders, autism spectrum disorder, and schizophrenia. The relationship between these outcomes and OFCs is poorly understood and controversial. Recent neuroimaging studies in humans and mice demonstrate subtle morphological brain abnormalities that co-occur with OFCs but specific molecular and cellular mechanisms have not been investigated. Here, we provide the first evidence directly linking OFC pathogenesis to abnormal development of GABAergic cortical interneurons (cINs). Lineage tracing revealed that the structures that form the upper lip and palate develop in molecular synchrony and spatiotemporal proximity to cINs, suggesting these populations may have shared sensitivity to genetic and/or teratogenic insult. Examination of cIN development in a mouse model of nonsyndromic OFCs revealed significant disruptions in cIN proliferation and migration, culminating in misspecification of the somatostatin-expressing subgroup. These findings reveal a unified developmental basis for orofacial clefting and disrupted cIN development, and may explain the significant overlap in neurobehavioral and psychiatric outcomes associated with OFCs and cIN dysfunction. This emerging mechanistic understanding for increased prevalence of adverse neurobehavioral outcomes in OFC patients is the entry-point for developing evidence-based therapies to improve patient outcomes. |
format | Online Article Text |
id | pubmed-5802454 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-58024542018-02-08 Common basis for orofacial clefting and cortical interneuronopathy Ansen-Wilson, Lydia J. Everson, Joshua L. Fink, Dustin M. Kietzman, Henry W. Sullivan, Ruth Lipinski, Robert J. Transl Psychiatry Article Orofacial clefts (OFCs) of the lip and/or palate are among the most common human birth defects. Current treatment strategies focus on functional and cosmetic repair but even when this care is available, individuals born with OFCs are at high risk for persistent neurobehavioral problems. In addition to learning disabilities and reduced academic achievement, recent evidence associates OFCs with elevated risk for a constellation of psychiatric outcomes including anxiety disorders, autism spectrum disorder, and schizophrenia. The relationship between these outcomes and OFCs is poorly understood and controversial. Recent neuroimaging studies in humans and mice demonstrate subtle morphological brain abnormalities that co-occur with OFCs but specific molecular and cellular mechanisms have not been investigated. Here, we provide the first evidence directly linking OFC pathogenesis to abnormal development of GABAergic cortical interneurons (cINs). Lineage tracing revealed that the structures that form the upper lip and palate develop in molecular synchrony and spatiotemporal proximity to cINs, suggesting these populations may have shared sensitivity to genetic and/or teratogenic insult. Examination of cIN development in a mouse model of nonsyndromic OFCs revealed significant disruptions in cIN proliferation and migration, culminating in misspecification of the somatostatin-expressing subgroup. These findings reveal a unified developmental basis for orofacial clefting and disrupted cIN development, and may explain the significant overlap in neurobehavioral and psychiatric outcomes associated with OFCs and cIN dysfunction. This emerging mechanistic understanding for increased prevalence of adverse neurobehavioral outcomes in OFC patients is the entry-point for developing evidence-based therapies to improve patient outcomes. Nature Publishing Group UK 2018-01-10 /pmc/articles/PMC5802454/ /pubmed/29317601 http://dx.doi.org/10.1038/s41398-017-0057-7 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Ansen-Wilson, Lydia J. Everson, Joshua L. Fink, Dustin M. Kietzman, Henry W. Sullivan, Ruth Lipinski, Robert J. Common basis for orofacial clefting and cortical interneuronopathy |
title | Common basis for orofacial clefting and cortical interneuronopathy |
title_full | Common basis for orofacial clefting and cortical interneuronopathy |
title_fullStr | Common basis for orofacial clefting and cortical interneuronopathy |
title_full_unstemmed | Common basis for orofacial clefting and cortical interneuronopathy |
title_short | Common basis for orofacial clefting and cortical interneuronopathy |
title_sort | common basis for orofacial clefting and cortical interneuronopathy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5802454/ https://www.ncbi.nlm.nih.gov/pubmed/29317601 http://dx.doi.org/10.1038/s41398-017-0057-7 |
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