FOXR1 regulates stress response pathways and is necessary for proper brain development

The forkhead box (Fox) family of transcription factors are highly conserved and play essential roles in a wide range of cellular and developmental processes. We report an individual with severe neurological symptoms including postnatal microcephaly, progressive brain atrophy and global developmental...

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Autores principales:	Andressa Mota, Hannah K. Waxman, Rui Hong, Gavin D. Lagani, Sheng-Yong Niu, Féodora L. Bertherat, Lynne Wolfe, Christine May Malicdan, Thomas C. Markello, David R. Adams, William A. Gahl, Christine S. Cheng, Uwe Beffert, Angela Ho
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/c1ff14fa39f34f54ada5c832ebbe40c8
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spelling	oai:doaj.org-article:c1ff14fa39f34f54ada5c832ebbe40c82021-11-11T06:16:25ZFOXR1 regulates stress response pathways and is necessary for proper brain development1553-73901553-7404https://doaj.org/article/c1ff14fa39f34f54ada5c832ebbe40c82021-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8559929/?tool=EBIhttps://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404The forkhead box (Fox) family of transcription factors are highly conserved and play essential roles in a wide range of cellular and developmental processes. We report an individual with severe neurological symptoms including postnatal microcephaly, progressive brain atrophy and global developmental delay associated with a de novo missense variant (M280L) in the FOXR1 gene. At the protein level, M280L impaired FOXR1 expression and induced a nuclear aggregate phenotype due to protein misfolding and proteolysis. RNAseq and pathway analysis showed that FOXR1 acts as a transcriptional activator and repressor with central roles in heat shock response, chaperone cofactor-dependent protein refolding and cellular response to stress pathways. Indeed, FOXR1 expression is increased in response to cellular stress, a process in which it directly controls HSPA6, HSPA1A and DHRS2 transcripts. The M280L mutant compromises FOXR1’s ability to respond to stress, in part due to impaired regulation of downstream target genes that are involved in the stress response pathway. Quantitative PCR of mouse embryo tissues show Foxr1 expression in the embryonic brain. Using CRISPR/Cas9 gene editing, we found that deletion of mouse Foxr1 leads to a severe survival deficit while surviving newborn Foxr1 knockout mice have reduced body weight. Further examination of newborn Foxr1 knockout brains revealed a decrease in cortical thickness and enlarged ventricles compared to littermate wild-type mice, suggesting that loss of Foxr1 leads to atypical brain development. Combined, these results suggest FOXR1 plays a role in cellular stress response pathways and is necessary for normal brain development. Author summary Exome sequencing of an individual with severe neurological symptoms including postnatal microcephaly, progressive brain atrophy, and global developmental delay implicated a de novo missense variant in the FOXR1 gene as potentially causative. FOXR1 is a member of the forkhead box (FOX) family of transcription factors with unknown function. Overexpression of FOXR1 in cultured cells show diffuse nuclear localization, while the FOXR1 mutant led to an accumulation of nuclear aggregates due to protein misfolding. As a transcription factor, FOXR1 was found to regulate a large number of genes including those involved in protein folding pathways, while the mutant showed impaired regulation of stress-responsive genes. Although FOXR1 is expressed at low levels in most tissues, we detected Foxr1 expression in mouse embryonic brain tissue. Using CRISPR gene editing, deletion of the Foxr1 gene in mice led to reduced survival at birth. Brain pathology of Foxr1 knockout mice revealed decreased cortical thickness and an enlargement of ventricles. Our data reveal that FOXR1 regulates genes involved in proper protein folding and lack of Foxr1 in mice is associated with reduced survival and brain pathology consistent with observations found in the human brain.Andressa MotaHannah K. WaxmanRui HongGavin D. LaganiSheng-Yong NiuFéodora L. BertheratLynne WolfeChristine May MalicdanThomas C. MarkelloDavid R. AdamsWilliam A. GahlChristine S. ChengUwe BeffertAngela HoPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Andressa Mota Hannah K. Waxman Rui Hong Gavin D. Lagani Sheng-Yong Niu Féodora L. Bertherat Lynne Wolfe Christine May Malicdan Thomas C. Markello David R. Adams William A. Gahl Christine S. Cheng Uwe Beffert Angela Ho FOXR1 regulates stress response pathways and is necessary for proper brain development
description	The forkhead box (Fox) family of transcription factors are highly conserved and play essential roles in a wide range of cellular and developmental processes. We report an individual with severe neurological symptoms including postnatal microcephaly, progressive brain atrophy and global developmental delay associated with a de novo missense variant (M280L) in the FOXR1 gene. At the protein level, M280L impaired FOXR1 expression and induced a nuclear aggregate phenotype due to protein misfolding and proteolysis. RNAseq and pathway analysis showed that FOXR1 acts as a transcriptional activator and repressor with central roles in heat shock response, chaperone cofactor-dependent protein refolding and cellular response to stress pathways. Indeed, FOXR1 expression is increased in response to cellular stress, a process in which it directly controls HSPA6, HSPA1A and DHRS2 transcripts. The M280L mutant compromises FOXR1’s ability to respond to stress, in part due to impaired regulation of downstream target genes that are involved in the stress response pathway. Quantitative PCR of mouse embryo tissues show Foxr1 expression in the embryonic brain. Using CRISPR/Cas9 gene editing, we found that deletion of mouse Foxr1 leads to a severe survival deficit while surviving newborn Foxr1 knockout mice have reduced body weight. Further examination of newborn Foxr1 knockout brains revealed a decrease in cortical thickness and enlarged ventricles compared to littermate wild-type mice, suggesting that loss of Foxr1 leads to atypical brain development. Combined, these results suggest FOXR1 plays a role in cellular stress response pathways and is necessary for normal brain development. Author summary Exome sequencing of an individual with severe neurological symptoms including postnatal microcephaly, progressive brain atrophy, and global developmental delay implicated a de novo missense variant in the FOXR1 gene as potentially causative. FOXR1 is a member of the forkhead box (FOX) family of transcription factors with unknown function. Overexpression of FOXR1 in cultured cells show diffuse nuclear localization, while the FOXR1 mutant led to an accumulation of nuclear aggregates due to protein misfolding. As a transcription factor, FOXR1 was found to regulate a large number of genes including those involved in protein folding pathways, while the mutant showed impaired regulation of stress-responsive genes. Although FOXR1 is expressed at low levels in most tissues, we detected Foxr1 expression in mouse embryonic brain tissue. Using CRISPR gene editing, deletion of the Foxr1 gene in mice led to reduced survival at birth. Brain pathology of Foxr1 knockout mice revealed decreased cortical thickness and an enlargement of ventricles. Our data reveal that FOXR1 regulates genes involved in proper protein folding and lack of Foxr1 in mice is associated with reduced survival and brain pathology consistent with observations found in the human brain.
format	article
author	Andressa Mota Hannah K. Waxman Rui Hong Gavin D. Lagani Sheng-Yong Niu Féodora L. Bertherat Lynne Wolfe Christine May Malicdan Thomas C. Markello David R. Adams William A. Gahl Christine S. Cheng Uwe Beffert Angela Ho
author_facet	Andressa Mota Hannah K. Waxman Rui Hong Gavin D. Lagani Sheng-Yong Niu Féodora L. Bertherat Lynne Wolfe Christine May Malicdan Thomas C. Markello David R. Adams William A. Gahl Christine S. Cheng Uwe Beffert Angela Ho
author_sort	Andressa Mota
title	FOXR1 regulates stress response pathways and is necessary for proper brain development
title_short	FOXR1 regulates stress response pathways and is necessary for proper brain development
title_full	FOXR1 regulates stress response pathways and is necessary for proper brain development
title_fullStr	FOXR1 regulates stress response pathways and is necessary for proper brain development
title_full_unstemmed	FOXR1 regulates stress response pathways and is necessary for proper brain development
title_sort	foxr1 regulates stress response pathways and is necessary for proper brain development
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/c1ff14fa39f34f54ada5c832ebbe40c8
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FOXR1 regulates stress response pathways and is necessary for proper brain development

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