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A myelin-related transcriptomic profile is shared by Pitt–Hopkins syndrome models and human autism spectrum disorder.

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Title: A myelin-related transcriptomic profile is shared by Pitt–Hopkins syndrome models and human autism spectrum disorder.
Authors: Phan, BaDoi N. (AUTHOR), Bohlen, Joseph F. (AUTHOR), Davis, Brittany A. (AUTHOR), Ye, Zengyou (AUTHOR), Chen, Huei-Ying (AUTHOR), Mayfield, Brent (AUTHOR), Sripathy, Srinidhi Rao (AUTHOR), Cerceo Page, Stephanie (AUTHOR), Campbell, Morganne N. (AUTHOR), Smith, Hannah L. (AUTHOR), Gallop, Danisha (AUTHOR), Kim, Hyojin (AUTHOR), Thaxton, Courtney L. (AUTHOR), Simon, Jeremy M. (AUTHOR), Burke, Emily E. (AUTHOR), Shin, Joo Heon (AUTHOR), Kennedy, Andrew J. (AUTHOR), Sweatt, J. David (AUTHOR), Philpot, Benjamin D. (AUTHOR), Jaffe, Andrew E. (AUTHOR)
Source: Nature Neuroscience. Mar2020, Vol. 23 Issue 3, p375-385. 11p. 2 Diagrams, 16 Graphs.
Abstract: Autism spectrum disorder (ASD) is genetically heterogeneous with convergent symptomatology, suggesting common dysregulated pathways. In this study, we analyzed brain transcriptional changes in five mouse models of Pitt–Hopkins syndrome (PTHS), a syndromic form of ASD caused by mutations in the TCF4 gene, but not the TCF7L2 gene. Analyses of differentially expressed genes (DEGs) highlighted oligodendrocyte (OL) dysregulation, which we confirmed in two additional mouse models of syndromic ASD (Ptenm3m4/m3m4 and Mecp2tm1.1Bird). The PTHS mouse models showed cell-autonomous reductions in OL numbers and myelination, functionally confirming OL transcriptional signatures. We also integrated PTHS mouse model DEGs with human idiopathic ASD postmortem brain RNA-sequencing data and found significant enrichment of overlapping DEGs and common myelination-associated pathways. Notably, DEGs from syndromic ASD mouse models and reduced deconvoluted OL numbers distinguished human idiopathic ASD cases from controls across three postmortem brain data sets. These results implicate disruptions in OL biology as a cellular mechanism in ASD pathology. The authors identify an impaired myelination signature from the brains of mouse models of Pitt–Hopkins syndrome and show that it is shared in the postmortem brains of people with autism. [ABSTRACT FROM AUTHOR]
Copyright of Nature Neuroscience is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: A myelin-related transcriptomic profile is shared by Pitt–Hopkins syndrome models and human autism spectrum disorder.
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  Data: <searchLink fieldCode="AR" term="%22Phan%2C+BaDoi+N%2E%22">Phan, BaDoi N.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Bohlen%2C+Joseph+F%2E%22">Bohlen, Joseph F.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Davis%2C+Brittany+A%2E%22">Davis, Brittany A.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Ye%2C+Zengyou%22">Ye, Zengyou</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Chen%2C+Huei-Ying%22">Chen, Huei-Ying</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Mayfield%2C+Brent%22">Mayfield, Brent</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Sripathy%2C+Srinidhi+Rao%22">Sripathy, Srinidhi Rao</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Cerceo+Page%2C+Stephanie%22">Cerceo Page, Stephanie</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Campbell%2C+Morganne+N%2E%22">Campbell, Morganne N.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Smith%2C+Hannah+L%2E%22">Smith, Hannah L.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Gallop%2C+Danisha%22">Gallop, Danisha</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Kim%2C+Hyojin%22">Kim, Hyojin</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Thaxton%2C+Courtney+L%2E%22">Thaxton, Courtney L.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Simon%2C+Jeremy+M%2E%22">Simon, Jeremy M.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Burke%2C+Emily+E%2E%22">Burke, Emily E.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Shin%2C+Joo+Heon%22">Shin, Joo Heon</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Kennedy%2C+Andrew+J%2E%22">Kennedy, Andrew J.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Sweatt%2C+J%2E+David%22">Sweatt, J. David</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Philpot%2C+Benjamin+D%2E%22">Philpot, Benjamin D.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Jaffe%2C+Andrew+E%2E%22">Jaffe, Andrew E.</searchLink> (AUTHOR)
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  Data: Autism spectrum disorder (ASD) is genetically heterogeneous with convergent symptomatology, suggesting common dysregulated pathways. In this study, we analyzed brain transcriptional changes in five mouse models of Pitt–Hopkins syndrome (PTHS), a syndromic form of ASD caused by mutations in the TCF4 gene, but not the TCF7L2 gene. Analyses of differentially expressed genes (DEGs) highlighted oligodendrocyte (OL) dysregulation, which we confirmed in two additional mouse models of syndromic ASD (Ptenm3m4/m3m4 and Mecp2tm1.1Bird). The PTHS mouse models showed cell-autonomous reductions in OL numbers and myelination, functionally confirming OL transcriptional signatures. We also integrated PTHS mouse model DEGs with human idiopathic ASD postmortem brain RNA-sequencing data and found significant enrichment of overlapping DEGs and common myelination-associated pathways. Notably, DEGs from syndromic ASD mouse models and reduced deconvoluted OL numbers distinguished human idiopathic ASD cases from controls across three postmortem brain data sets. These results implicate disruptions in OL biology as a cellular mechanism in ASD pathology. The authors identify an impaired myelination signature from the brains of mouse models of Pitt–Hopkins syndrome and show that it is shared in the postmortem brains of people with autism. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Nature Neuroscience is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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