Early role for a Na+,K+-ATPase (ATP1A3) in brain development
Richard S. Smith, Marta Florio, Shyam K. Akula, Jennifer E. Neil, Yidi Wang, R. Sean Hill, Melissa Goldman, Christopher D. Mullally, Nora Reed, Luis Bello-Espinosa, Laura Flores-Sarnat, Fabiola Paoli Monteiro, Casella B. Erasmo, Filippo Pinto e Vairo, Eva Morava, A. James Barkovich, Joseph Gonzalez-Heydrich, Catherine A. Brownstein, Steven A. McCarroll, Christopher A. Walsh
Abstract
Osmotic equilibrium and membrane potential in animal cells depend on concentration gradients of sodium (Na+) and potassium (K+) ions across the plasma membrane, a function catalyzed by the Na+,K+-ATPase α-subunit. Here, we describe ATP1A3 variants encoding dysfunctional α3-subunits in children affected by polymicrogyria, a developmental malformation of the cerebral cortex characterized by abnormal folding and laminar organization. To gain cell-biological insights into the spatiotemporal dynamics of prenatal ATP1A3 expression, we built an ATP1A3 transcriptional atlas of fetal cortical development using mRNA in situ hybridization and transcriptomic profiling of ∼125,000 individual cells with single-cell RNA sequencing (Drop-seq) from 11 areas of the midgestational human neocortex. We found that fetal expression of ATP1A3 is most abundant to a subset of excitatory neurons carrying transcriptional signatures of the developing subplate, yet also maintains expression in nonneuronal cell populations. Moving forward a year in human development, we profiled ∼52,000 nuclei from four areas of an infant neocortex and show that ATP1A3 expression persists throughout early postnatal development, most predominantly in inhibitory neurons, including parvalbumin interneurons in the frontal cortex. Finally, we discovered the heteromeric Na+,K+-ATPase pump complex may form nonredundant cell-type–specific α-β isoform combinations, including α3-β1 in excitatory neurons and α3-β2 in inhibitory neurons. Together, the developmental malformation phenotype of affected individuals and single-cell ATP1A3 expression patterns point to a key role for α3 in human cortex development, as well as a cell-type basis for pre- and postnatal ATP1A3-associated diseases.
Datasets
1. Midgestational human neocortex cells
2. Infant human neocortex cells
Analyze this study
Source data
https://cellxgene.cziscience.com/collections/e02201d7-f49f-401f-baf0-1eb1406546c0
Alias names
phs001272, PMID34161264, PMC8237684
Cite this study
Smith, R.S., Florio, M., Akula, S.K., Neil, J.E., Wang, Y., Hill, R.S., Goldman, M., Mullally, C.D., Reed, N., Bello-Espinosa, L. and Flores-Sarnat, L., 2021. Early role for a Na+, K+-ATPase (ATP1A3) in brain development. Proceedings of the National Academy of Sciences, 118(25), p.e2023333118. https://doi.org/10.1073/pnas.2023333118