Valproic acid exposure decreases neurogenic potential of outer radial glia in human brain organoids
Valproic acid (VPA) exposure during pregnancy leads to a higher risk of autism spectrum disorder (ASD) susceptibility in offspring. Human dorsal forebrain organoids were used to recapitulate course of cortical neurogenesis in the developing human brain. Combining morphological characterization with...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2022.1023765/full |
| _version_ | 1798015997937975296 |
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| author | Zhenle Zang Zhenle Zang Huachun Yin Zhulin Du Ruxin Xie Ling Yang Yun Cai Liuyongwei Wang Dandan Zhang Xin Li Tianyao Liu Hong Gong Junwei Gao Hui Yang Margaret Warner Jan-Ake Gustafsson Jan-Ake Gustafsson Haiwei Xu Xiaotang Fan |
| author_facet | Zhenle Zang Zhenle Zang Huachun Yin Zhulin Du Ruxin Xie Ling Yang Yun Cai Liuyongwei Wang Dandan Zhang Xin Li Tianyao Liu Hong Gong Junwei Gao Hui Yang Margaret Warner Jan-Ake Gustafsson Jan-Ake Gustafsson Haiwei Xu Xiaotang Fan |
| author_sort | Zhenle Zang |
| collection | DOAJ |
| description | Valproic acid (VPA) exposure during pregnancy leads to a higher risk of autism spectrum disorder (ASD) susceptibility in offspring. Human dorsal forebrain organoids were used to recapitulate course of cortical neurogenesis in the developing human brain. Combining morphological characterization with massive parallel RNA sequencing (RNA-seq) on organoids to analyze the pathogenic effects caused by VPA exposure and critical signaling pathway. We found that VPA exposure in organoids caused a reduction in the size and impairment in the proliferation and expansion of neural progenitor cells (NPCs) in a dose-dependent manner. VPA exposure typically decreased the production of outer radial glia-like cells (oRGs), a subtype of NPCs contributing to mammalian neocortical expansion and delayed their fate toward upper-layer neurons. Transcriptomics analysis revealed that VPA exposure influenced ASD risk gene expression in organoids, which markedly overlapped with irregulated genes in brains or organoids originating from ASD patients. We also identified that VPA-mediated Wnt/β-catenin signaling pathway activation is essential for sustaining cortical neurogenesis and oRGs output. Taken together, our study establishes the use of dorsal forebrain organoids as an effective platform for modeling VPA-induced teratogenic pathways involved in the cortical neurogenesis and oRGs output, which might contribute to ASD pathogenesis in the developing brain. |
| first_indexed | 2024-04-11T15:43:42Z |
| format | Article |
| id | doaj.art-7875d3f5d05146f08e2b5231e1db2430 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-04-11T15:43:42Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-7875d3f5d05146f08e2b5231e1db24302022-12-22T04:15:40ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992022-11-011510.3389/fnmol.2022.10237651023765Valproic acid exposure decreases neurogenic potential of outer radial glia in human brain organoidsZhenle Zang0Zhenle Zang1Huachun Yin2Zhulin Du3Ruxin Xie4Ling Yang5Yun Cai6Liuyongwei Wang7Dandan Zhang8Xin Li9Tianyao Liu10Hong Gong11Junwei Gao12Hui Yang13Margaret Warner14Jan-Ake Gustafsson15Jan-Ake Gustafsson16Haiwei Xu17Xiaotang Fan18Department of Developmental Neuropsychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, ChinaDepartment of Neurosurgery, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, ChinaDepartment of Neurosurgery, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, ChinaDepartment of Developmental Neuropsychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, ChinaDepartment of Developmental Neuropsychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, ChinaDepartment of Developmental Neuropsychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, ChinaDepartment of Developmental Neuropsychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, ChinaDepartment of Developmental Neuropsychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, ChinaDepartment of Developmental Neuropsychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, ChinaDepartment of Developmental Neuropsychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, ChinaDepartment of Developmental Neuropsychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, ChinaDepartment of Developmental Neuropsychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, ChinaDepartment of Developmental Neuropsychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, ChinaDepartment of Neurosurgery, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, ChinaCenter for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, United StatesCenter for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, United StatesDepartment of Biosciences and Nutrition, Karolinska Institute, Huddinge, SwedenSouthwest Hospital and Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, ChinaDepartment of Developmental Neuropsychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, ChinaValproic acid (VPA) exposure during pregnancy leads to a higher risk of autism spectrum disorder (ASD) susceptibility in offspring. Human dorsal forebrain organoids were used to recapitulate course of cortical neurogenesis in the developing human brain. Combining morphological characterization with massive parallel RNA sequencing (RNA-seq) on organoids to analyze the pathogenic effects caused by VPA exposure and critical signaling pathway. We found that VPA exposure in organoids caused a reduction in the size and impairment in the proliferation and expansion of neural progenitor cells (NPCs) in a dose-dependent manner. VPA exposure typically decreased the production of outer radial glia-like cells (oRGs), a subtype of NPCs contributing to mammalian neocortical expansion and delayed their fate toward upper-layer neurons. Transcriptomics analysis revealed that VPA exposure influenced ASD risk gene expression in organoids, which markedly overlapped with irregulated genes in brains or organoids originating from ASD patients. We also identified that VPA-mediated Wnt/β-catenin signaling pathway activation is essential for sustaining cortical neurogenesis and oRGs output. Taken together, our study establishes the use of dorsal forebrain organoids as an effective platform for modeling VPA-induced teratogenic pathways involved in the cortical neurogenesis and oRGs output, which might contribute to ASD pathogenesis in the developing brain.https://www.frontiersin.org/articles/10.3389/fnmol.2022.1023765/fullvalproic aciddorsal forebrain organoidneurogenesisautism spectrum disorderouter radial glia |
| spellingShingle | Zhenle Zang Zhenle Zang Huachun Yin Zhulin Du Ruxin Xie Ling Yang Yun Cai Liuyongwei Wang Dandan Zhang Xin Li Tianyao Liu Hong Gong Junwei Gao Hui Yang Margaret Warner Jan-Ake Gustafsson Jan-Ake Gustafsson Haiwei Xu Xiaotang Fan Valproic acid exposure decreases neurogenic potential of outer radial glia in human brain organoids Frontiers in Molecular Neuroscience valproic acid dorsal forebrain organoid neurogenesis autism spectrum disorder outer radial glia |
| title | Valproic acid exposure decreases neurogenic potential of outer radial glia in human brain organoids |
| title_full | Valproic acid exposure decreases neurogenic potential of outer radial glia in human brain organoids |
| title_fullStr | Valproic acid exposure decreases neurogenic potential of outer radial glia in human brain organoids |
| title_full_unstemmed | Valproic acid exposure decreases neurogenic potential of outer radial glia in human brain organoids |
| title_short | Valproic acid exposure decreases neurogenic potential of outer radial glia in human brain organoids |
| title_sort | valproic acid exposure decreases neurogenic potential of outer radial glia in human brain organoids |
| topic | valproic acid dorsal forebrain organoid neurogenesis autism spectrum disorder outer radial glia |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2022.1023765/full |
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