Aberrant Gcm1 expression mediates Wnt/β-catenin pathway activation in folate deficiency involved in neural tube defects

Abstract Wnt signaling plays a major role in early neural development. An aberrant activation in Wnt/β-catenin pathway causes defective anteroposterior patterning, which results in neural tube closure defects (NTDs). Changes in folate metabolism may participate in early embryo fate determination. We...

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Main Authors:	Jianting Li, Qiu Xie, Jun Gao, Fang Wang, Yihua Bao, Lihua Wu, Lihong Yang, Zhizhen Liu, Rui Guo, Ajab Khan, Dan Liu, Caihua Li, Jianxin Wu, Jun Xie
Format:	Article
Language:	English
Published:	Nature Publishing Group 2021-03-01
Series:	Cell Death and Disease
Online Access:	https://doi.org/10.1038/s41419-020-03313-z

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spelling	doaj-b8ad3e8ec5a14d61a6f732b4844c5a822021-03-11T11:16:23ZengNature Publishing GroupCell Death and Disease2041-48892021-03-0112311610.1038/s41419-020-03313-zAberrant Gcm1 expression mediates Wnt/β-catenin pathway activation in folate deficiency involved in neural tube defectsJianting Li0Qiu Xie1Jun Gao2Fang Wang3Yihua Bao4Lihua Wu5Lihong Yang6Zhizhen Liu7Rui Guo8Ajab Khan9Dan Liu10Caihua Li11Jianxin Wu12Jun Xie13Department of Biochemistry and Molecular Biology, Shanxi Medical UniversityDepartment of medical research center, Peking Union Medical College Hospital, Chinese Academy of Medical SciencesDepartment of Postgraduate, Weifang Medical UniversityBeijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of PediatricsBeijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of PediatricsBeijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of PediatricsDepartment of Pathology, Shanxi Medical UniversityDepartment of Biochemistry and Molecular Biology, Shanxi Medical UniversityDepartment of Biochemistry and Molecular Biology, Shanxi Medical UniversityDepartment of Biochemistry and Molecular Biology, Shanxi Medical UniversityDepartment of Biochemistry and Molecular Biology, Shanxi Medical UniversityDepartment of Bioinformatics, Genesky Biotechnologies IncBeijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of PediatricsDepartment of Biochemistry and Molecular Biology, Shanxi Medical UniversityAbstract Wnt signaling plays a major role in early neural development. An aberrant activation in Wnt/β-catenin pathway causes defective anteroposterior patterning, which results in neural tube closure defects (NTDs). Changes in folate metabolism may participate in early embryo fate determination. We have identified that folate deficiency activated Wnt/β-catenin pathway by upregulating a chorion-specific transcription factor Gcm1. Specifically, folate deficiency promoted formation of the Gcm1/β-catenin/T-cell factor (TCF4) complex formation to regulate the Wnt targeted gene transactivation through Wnt-responsive elements. Moreover, the transcription factor Nanog upregulated Gcm1 transcription in mESCs under folate deficiency. Lastly, in NTDs mouse models and low-folate NTDs human brain samples, Gcm1 and Wnt/β-catenin targeted genes related to neural tube closure are specifically overexpressed. These results indicated that low-folate level promoted Wnt/β-catenin signaling via activating Gcm1, and thus leaded into aberrant vertebrate neural development.https://doi.org/10.1038/s41419-020-03313-z
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Jianting Li Qiu Xie Jun Gao Fang Wang Yihua Bao Lihua Wu Lihong Yang Zhizhen Liu Rui Guo Ajab Khan Dan Liu Caihua Li Jianxin Wu Jun Xie
spellingShingle	Jianting Li Qiu Xie Jun Gao Fang Wang Yihua Bao Lihua Wu Lihong Yang Zhizhen Liu Rui Guo Ajab Khan Dan Liu Caihua Li Jianxin Wu Jun Xie Aberrant Gcm1 expression mediates Wnt/β-catenin pathway activation in folate deficiency involved in neural tube defects Cell Death and Disease
author_facet	Jianting Li Qiu Xie Jun Gao Fang Wang Yihua Bao Lihua Wu Lihong Yang Zhizhen Liu Rui Guo Ajab Khan Dan Liu Caihua Li Jianxin Wu Jun Xie
author_sort	Jianting Li
title	Aberrant Gcm1 expression mediates Wnt/β-catenin pathway activation in folate deficiency involved in neural tube defects
title_short	Aberrant Gcm1 expression mediates Wnt/β-catenin pathway activation in folate deficiency involved in neural tube defects
title_full	Aberrant Gcm1 expression mediates Wnt/β-catenin pathway activation in folate deficiency involved in neural tube defects
title_fullStr	Aberrant Gcm1 expression mediates Wnt/β-catenin pathway activation in folate deficiency involved in neural tube defects
title_full_unstemmed	Aberrant Gcm1 expression mediates Wnt/β-catenin pathway activation in folate deficiency involved in neural tube defects
title_sort	aberrant gcm1 expression mediates wnt/β-catenin pathway activation in folate deficiency involved in neural tube defects
publisher	Nature Publishing Group
series	Cell Death and Disease
issn	2041-4889
publishDate	2021-03-01
description	Abstract Wnt signaling plays a major role in early neural development. An aberrant activation in Wnt/β-catenin pathway causes defective anteroposterior patterning, which results in neural tube closure defects (NTDs). Changes in folate metabolism may participate in early embryo fate determination. We have identified that folate deficiency activated Wnt/β-catenin pathway by upregulating a chorion-specific transcription factor Gcm1. Specifically, folate deficiency promoted formation of the Gcm1/β-catenin/T-cell factor (TCF4) complex formation to regulate the Wnt targeted gene transactivation through Wnt-responsive elements. Moreover, the transcription factor Nanog upregulated Gcm1 transcription in mESCs under folate deficiency. Lastly, in NTDs mouse models and low-folate NTDs human brain samples, Gcm1 and Wnt/β-catenin targeted genes related to neural tube closure are specifically overexpressed. These results indicated that low-folate level promoted Wnt/β-catenin signaling via activating Gcm1, and thus leaded into aberrant vertebrate neural development.
url	https://doi.org/10.1038/s41419-020-03313-z
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Aberrant Gcm1 expression mediates Wnt/β-catenin pathway activation in folate deficiency involved in neural tube defects

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