Developmental dynamics of voltage-gated sodium channel isoform expression in the human and mouse neocortex
Developmental dynamics of voltage-gated sodium channel isoform expression in the human and mouse neocortex
Abstract ObjectiveGenetic variants in the voltage-gated sodium channels SCN1A, SCN2A, SCN3A, and SCN8A are leading causes of epilepsy, developmental delay, and autism spectrum disorder. The mRNA splicing patterns of all four genes vary across development in the rodent brain, including mutually exclusive copies of the fifth protein-coding exon detected in the neonate (5N) and adult (5A). A second pair of mutually exclusive exons is reported in SCN8A only (18N and 18A). We aimed to quantify the expression of individual exons in the developing human neocortex. MethodsRNA-seq data from 176 human dorsolateral prefrontal cortex samples across development were analyzed to estimate exon-level expression. Developmental changes in exon utilization were validated by assessing intron splicing. Exon expression was also estimated in RNA-seq data from 58 developing mouse neocortical samples. ResultsIn the mature human neocortex, exon 5A is consistently expressed at least 4-fold higher than exon 5N in all four genes. For SCN2A, SCN3A, and SCN8A a synchronized 5N/5A transition occurs between 24 post-conceptual weeks (2nd trimester) and six years of age. In mice, the equivalent 5N/5A transition begins at or before embryonic day 15.5. In SCN8A, over 90% of transcripts in the mature human cortex include exon 18A. Early in fetal development, most transcripts include 18N or skip both 18N and 18A, with a transition to 18A inclusion occurring from 13 post-conceptual weeks to 6 months of age. No other protein-coding exons showed comparably dynamic developmental trajectories. SignificanceSplice isoforms, which alter the biophysical properties of the encoded channels, may account for some of the observed phenotypic differences across development and between specific variants. Manipulation of the proportion of splicing isoforms at appropriate stages of development may act as a therapeutic strategy for specific mutations or even epilepsy in general.
Gilson Michael C.、Rubenstein John L.R.、?estan Nenad、Liang Lindsay、Sahagun Atehsa、An Joon-Yong、Werling Donna M.、Darbandi Siavash Fazel、Sheppard Brooke K.、Gulden Forrest O.、Pochareddy Sirisha、Bender Kevin J.、Sanders Stephan J.
Department of Psychiatry and Behavioral Sciences, University of CaliforniaDepartment of Psychiatry and Behavioral Sciences, University of CaliforniaDepartment of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine||Program in Cellular Neuroscience, Neurodegeneration, and Repair and Yale Child Study Center, Yale School of Medicine||Department of Psychiatry, Yale University School of Medicine||Department of Genetics, Yale University School of Medicine||Department of Comparative Medicine, Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of MedicineDepartment of Psychiatry and Behavioral Sciences, University of CaliforniaDepartment of Neurology, University of California, San FranciscoSchool of Biosystem and Biomedical Science, College of Health Science, Korea UniversityLaboratory of Genetics, University of Wisconsin-MadisonDepartment of Psychiatry and Behavioral Sciences, University of CaliforniaDepartment of Psychiatry and Behavioral Sciences, University of CaliforniaDepartment of Neuroscience and Kavli Institute for Neuroscience, Yale School of MedicineDepartment of Neuroscience and Kavli Institute for Neuroscience, Yale School of MedicineDepartment of Neurology, University of California, San FranciscoDepartment of Psychiatry and Behavioral Sciences, University of California||Institute for Human Genetics, University of California||Bakar Computational Health Sciences Institute, University of California
基础医学神经病学、精神病学分子生物学
isoformsplicingepilepsyneurodevelopmental disordersSCN1ASCN2ASCN3ASCN8A5A5N18A18N
Gilson Michael C.,Rubenstein John L.R.,?estan Nenad,Liang Lindsay,Sahagun Atehsa,An Joon-Yong,Werling Donna M.,Darbandi Siavash Fazel,Sheppard Brooke K.,Gulden Forrest O.,Pochareddy Sirisha,Bender Kevin J.,Sanders Stephan J..Developmental dynamics of voltage-gated sodium channel isoform expression in the human and mouse neocortex[EB/OL].(2025-03-28)[2025-08-03].https://www.biorxiv.org/content/10.1101/2020.11.18.389171.点此复制
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