Deficiency of FABP7 Triggers Premature Neural Differentiation in Idiopathic Normocephalic Autism Organoids
Abstract Autism spectrum disorder (ASD), which is caused by heterogeneous genetic and environmental factors, is characterized by diverse clinical phenotypes linked to distinct pathological mechanisms. ASD individuals with a shared clinical phenotype might contribute to revealing the molecular mechan...
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| Format: | Article |
| Language: | English |
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Wiley
2025-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202406849 |
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| author | Xiao Han Yuanlin He Yuanhao Wang Wenzhu Hu Chu Chu Lei Huang Yuan Hong Lu Han Xu Zhang Yao Gao Yuan Lin Hongxia Ma Hongbing Shen Xiaoyan Ke Yan Liu Zhibin Hu |
| author_facet | Xiao Han Yuanlin He Yuanhao Wang Wenzhu Hu Chu Chu Lei Huang Yuan Hong Lu Han Xu Zhang Yao Gao Yuan Lin Hongxia Ma Hongbing Shen Xiaoyan Ke Yan Liu Zhibin Hu |
| author_sort | Xiao Han |
| collection | DOAJ |
| description | Abstract Autism spectrum disorder (ASD), which is caused by heterogeneous genetic and environmental factors, is characterized by diverse clinical phenotypes linked to distinct pathological mechanisms. ASD individuals with a shared clinical phenotype might contribute to revealing the molecular mechanism underlying ASD progression. Here, it is generated induced pluripotent stem cell (iPSC)‐derived cerebral organoids from normocephalic individuals with ASD in a prospective birth cohort with a shared clinical diagnosis. Multiple cell lines and time series scRNA‐seq combined with a histomorphological analysis revealed premature neural differentiation of neural stem cells (NSCs) and decreased expression of Fatty acid binding protein 7 (FABP7) in ASD organoids. It is subsequently revealed alterations in the phosphorylation levels of Mitogen‐Activated Protein Kinase Kinase 1/2 (MEK1/2), which are downstream of FABP7, and the regulation of the FABP7/MEK pathway reversed improper neural differentiation in the ASD organoids. Moreover, both Fabp7‐knockdown and MEK2‐overexpressing mice exhibited repetitive stereotyped behaviors and social defects relevant to autism. This study reveals the role of the FABP7/MEK pathway in abnormal NSC differentiation in normocephalic individuals with ASD, which might provide a promising therapeutic target for ASD treatment. |
| format | Article |
| id | doaj-art-77b0c0507e5940eab92b84cda8d46a5a |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-77b0c0507e5940eab92b84cda8d46a5a2025-01-13T15:29:43ZengWileyAdvanced Science2198-38442025-01-01122n/an/a10.1002/advs.202406849Deficiency of FABP7 Triggers Premature Neural Differentiation in Idiopathic Normocephalic Autism OrganoidsXiao Han0Yuanlin He1Yuanhao Wang2Wenzhu Hu3Chu Chu4Lei Huang5Yuan Hong6Lu Han7Xu Zhang8Yao Gao9Yuan Lin10Hongxia Ma11Hongbing Shen12Xiaoyan Ke13Yan Liu14Zhibin Hu15Interdisciplinary Inno Center for Organoids, State Key Laboratory of Reproductive Medicine and Offspring Health Nanjing Medical University Nanjing 211166 ChinaInterdisciplinary Inno Center for Organoids, State Key Laboratory of Reproductive Medicine and Offspring Health Nanjing Medical University Nanjing 211166 ChinaInterdisciplinary Inno Center for Organoids, State Key Laboratory of Reproductive Medicine and Offspring Health Nanjing Medical University Nanjing 211166 ChinaDepartment of Epidemiology and Biostatistics, Center for Global Health, School of Public Health Nanjing Medical University Nanjing 211166 ChinaInstitute of Stem Cell and Neural Regeneration, School of Pharmacy Nanjing Medical University Nanjing 211166 ChinaInterdisciplinary Inno Center for Organoids, State Key Laboratory of Reproductive Medicine and Offspring Health Nanjing Medical University Nanjing 211166 ChinaInstitute of Stem Cell and Neural Regeneration, School of Pharmacy Nanjing Medical University Nanjing 211166 ChinaAutism Research Center, State Key Laboratory of Reproductive Medicine The Affiliated Brain Hospital of Nanjing Medical University Nanjing 210029 ChinaInterdisciplinary Inno Center for Organoids, State Key Laboratory of Reproductive Medicine and Offspring Health Nanjing Medical University Nanjing 211166 ChinaDepartment of Epidemiology and Biostatistics, Center for Global Health, School of Public Health Nanjing Medical University Nanjing 211166 ChinaInterdisciplinary Inno Center for Organoids, State Key Laboratory of Reproductive Medicine and Offspring Health Nanjing Medical University Nanjing 211166 ChinaInterdisciplinary Inno Center for Organoids, State Key Laboratory of Reproductive Medicine and Offspring Health Nanjing Medical University Nanjing 211166 ChinaDepartment of Epidemiology and Biostatistics, Center for Global Health, School of Public Health Nanjing Medical University Nanjing 211166 ChinaAutism Research Center, State Key Laboratory of Reproductive Medicine The Affiliated Brain Hospital of Nanjing Medical University Nanjing 210029 ChinaInterdisciplinary Inno Center for Organoids, State Key Laboratory of Reproductive Medicine and Offspring Health Nanjing Medical University Nanjing 211166 ChinaInterdisciplinary Inno Center for Organoids, State Key Laboratory of Reproductive Medicine and Offspring Health Nanjing Medical University Nanjing 211166 ChinaAbstract Autism spectrum disorder (ASD), which is caused by heterogeneous genetic and environmental factors, is characterized by diverse clinical phenotypes linked to distinct pathological mechanisms. ASD individuals with a shared clinical phenotype might contribute to revealing the molecular mechanism underlying ASD progression. Here, it is generated induced pluripotent stem cell (iPSC)‐derived cerebral organoids from normocephalic individuals with ASD in a prospective birth cohort with a shared clinical diagnosis. Multiple cell lines and time series scRNA‐seq combined with a histomorphological analysis revealed premature neural differentiation of neural stem cells (NSCs) and decreased expression of Fatty acid binding protein 7 (FABP7) in ASD organoids. It is subsequently revealed alterations in the phosphorylation levels of Mitogen‐Activated Protein Kinase Kinase 1/2 (MEK1/2), which are downstream of FABP7, and the regulation of the FABP7/MEK pathway reversed improper neural differentiation in the ASD organoids. Moreover, both Fabp7‐knockdown and MEK2‐overexpressing mice exhibited repetitive stereotyped behaviors and social defects relevant to autism. This study reveals the role of the FABP7/MEK pathway in abnormal NSC differentiation in normocephalic individuals with ASD, which might provide a promising therapeutic target for ASD treatment.https://doi.org/10.1002/advs.202406849autism spectrum disordercerebral organoidFABP7normocephalypremature neural differentiation |
| spellingShingle | Xiao Han Yuanlin He Yuanhao Wang Wenzhu Hu Chu Chu Lei Huang Yuan Hong Lu Han Xu Zhang Yao Gao Yuan Lin Hongxia Ma Hongbing Shen Xiaoyan Ke Yan Liu Zhibin Hu Deficiency of FABP7 Triggers Premature Neural Differentiation in Idiopathic Normocephalic Autism Organoids Advanced Science autism spectrum disorder cerebral organoid FABP7 normocephaly premature neural differentiation |
| title | Deficiency of FABP7 Triggers Premature Neural Differentiation in Idiopathic Normocephalic Autism Organoids |
| title_full | Deficiency of FABP7 Triggers Premature Neural Differentiation in Idiopathic Normocephalic Autism Organoids |
| title_fullStr | Deficiency of FABP7 Triggers Premature Neural Differentiation in Idiopathic Normocephalic Autism Organoids |
| title_full_unstemmed | Deficiency of FABP7 Triggers Premature Neural Differentiation in Idiopathic Normocephalic Autism Organoids |
| title_short | Deficiency of FABP7 Triggers Premature Neural Differentiation in Idiopathic Normocephalic Autism Organoids |
| title_sort | deficiency of fabp7 triggers premature neural differentiation in idiopathic normocephalic autism organoids |
| topic | autism spectrum disorder cerebral organoid FABP7 normocephaly premature neural differentiation |
| url | https://doi.org/10.1002/advs.202406849 |
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