Mitotic block and epigenetic repression underlie neurodevelopmental defects and neurobehavioral deficits in congenital heart disease
Abstract Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease associated with microcephaly and poor neurodevelopmental outcomes. Here we show that the Ohia HLHS mouse model, with mutations in Sap130, a chromatin modifier, and Pcdha9, a cell adhesion protein, also exhibits micr...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55741-6 |
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| author | George C. Gabriel Hisato Yagi Tuantuan Tan Abha Bais Benjamin J. Glennon Margaret C. Stapleton Lihua Huang William T. Reynolds Marla G. Shaffer Madhavi Ganapathiraju Dennis Simon Ashok Panigrahy Yijen L. Wu Cecilia W. Lo |
| author_facet | George C. Gabriel Hisato Yagi Tuantuan Tan Abha Bais Benjamin J. Glennon Margaret C. Stapleton Lihua Huang William T. Reynolds Marla G. Shaffer Madhavi Ganapathiraju Dennis Simon Ashok Panigrahy Yijen L. Wu Cecilia W. Lo |
| author_sort | George C. Gabriel |
| collection | DOAJ |
| description | Abstract Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease associated with microcephaly and poor neurodevelopmental outcomes. Here we show that the Ohia HLHS mouse model, with mutations in Sap130, a chromatin modifier, and Pcdha9, a cell adhesion protein, also exhibits microcephaly associated with mitotic block and increased apoptosis leading to impaired cortical neurogenesis. Transcriptome profiling, DNA methylation, and Sap130 ChIPseq analyses all demonstrate dysregulation of genes associated with autism and cognitive impairment. This includes perturbation of REST transcriptional regulation of neurogenesis, disruption of CREB signaling regulating synaptic plasticity, and defects in neurovascular coupling mediating cerebral blood flow. Adult mice harboring either the Pcdha9 mutation, which show normal brain anatomy, or forebrain-specific Sap130 deletion via Emx1-Cre, which show microcephaly, both demonstrate learning and memory deficits and autism-like behavior. These findings provide mechanistic insights indicating the adverse neurodevelopment in HLHS may involve cell autonomous/nonautonomous defects and epigenetic dysregulation. |
| format | Article |
| id | doaj-art-94967ff39368460f878366b9dc04da9b |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-94967ff39368460f878366b9dc04da9b2025-01-12T12:30:17ZengNature PortfolioNature Communications2041-17232025-01-0116111910.1038/s41467-024-55741-6Mitotic block and epigenetic repression underlie neurodevelopmental defects and neurobehavioral deficits in congenital heart diseaseGeorge C. Gabriel0Hisato Yagi1Tuantuan Tan2Abha Bais3Benjamin J. Glennon4Margaret C. Stapleton5Lihua Huang6William T. Reynolds7Marla G. Shaffer8Madhavi Ganapathiraju9Dennis Simon10Ashok Panigrahy11Yijen L. Wu12Cecilia W. Lo13Department of Pediatrics and Department of Developmental Biology, University of PittsburghDepartment of Pediatrics and Department of Developmental Biology, University of PittsburghDepartment of Pediatrics and Department of Developmental Biology, University of PittsburghDepartment of Pediatrics and Department of Developmental Biology, University of PittsburghDepartment of Pediatrics and Department of Developmental Biology, University of PittsburghDepartment of Pediatrics and Department of Developmental Biology, University of PittsburghChinese University of Hong KongDepartment of Pediatrics and Department of Developmental Biology, University of PittsburghDepartment of Pediatrics and Department of Developmental Biology, University of PittsburghDepartment of Biomedical Informatics, University of PittsburghDepartment of Critical Care Medicine, University of PittsburghDepartment of Radiology, University of PittsburghDepartment of Pediatrics and Department of Developmental Biology, University of PittsburghDepartment of Pediatrics and Department of Developmental Biology, University of PittsburghAbstract Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease associated with microcephaly and poor neurodevelopmental outcomes. Here we show that the Ohia HLHS mouse model, with mutations in Sap130, a chromatin modifier, and Pcdha9, a cell adhesion protein, also exhibits microcephaly associated with mitotic block and increased apoptosis leading to impaired cortical neurogenesis. Transcriptome profiling, DNA methylation, and Sap130 ChIPseq analyses all demonstrate dysregulation of genes associated with autism and cognitive impairment. This includes perturbation of REST transcriptional regulation of neurogenesis, disruption of CREB signaling regulating synaptic plasticity, and defects in neurovascular coupling mediating cerebral blood flow. Adult mice harboring either the Pcdha9 mutation, which show normal brain anatomy, or forebrain-specific Sap130 deletion via Emx1-Cre, which show microcephaly, both demonstrate learning and memory deficits and autism-like behavior. These findings provide mechanistic insights indicating the adverse neurodevelopment in HLHS may involve cell autonomous/nonautonomous defects and epigenetic dysregulation.https://doi.org/10.1038/s41467-024-55741-6 |
| spellingShingle | George C. Gabriel Hisato Yagi Tuantuan Tan Abha Bais Benjamin J. Glennon Margaret C. Stapleton Lihua Huang William T. Reynolds Marla G. Shaffer Madhavi Ganapathiraju Dennis Simon Ashok Panigrahy Yijen L. Wu Cecilia W. Lo Mitotic block and epigenetic repression underlie neurodevelopmental defects and neurobehavioral deficits in congenital heart disease Nature Communications |
| title | Mitotic block and epigenetic repression underlie neurodevelopmental defects and neurobehavioral deficits in congenital heart disease |
| title_full | Mitotic block and epigenetic repression underlie neurodevelopmental defects and neurobehavioral deficits in congenital heart disease |
| title_fullStr | Mitotic block and epigenetic repression underlie neurodevelopmental defects and neurobehavioral deficits in congenital heart disease |
| title_full_unstemmed | Mitotic block and epigenetic repression underlie neurodevelopmental defects and neurobehavioral deficits in congenital heart disease |
| title_short | Mitotic block and epigenetic repression underlie neurodevelopmental defects and neurobehavioral deficits in congenital heart disease |
| title_sort | mitotic block and epigenetic repression underlie neurodevelopmental defects and neurobehavioral deficits in congenital heart disease |
| url | https://doi.org/10.1038/s41467-024-55741-6 |
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