Developmental HCN channelopathy results in decreased neural progenitor proliferation and microcephaly in mice
The development of the cerebral cortex relies on the controlled division of neural stem and progenitor cells. The requirement for precise spatiotemporal control of proliferation and cell fate places a high demand on the cell division machinery, and defective cell division can cause microcephaly and...
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| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
Ausgust 24, 2021
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| In: |
Proceedings of the National Academy of Sciences of the United States of America
Year: 2021, Volume: 118, Issue: 35, Pages: 1-12 |
| ISSN: | 1091-6490 |
| DOI: | 10.1073/pnas.2009393118 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1073/pnas.2009393118 Verlag, lizenzpflichtig, Volltext: https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=DynamicDOIArticle&SrcApp=WOS&KeyAID=10.1073%2Fpnas.2009393118&DestApp=DOI&SrcAppSID=C2yARAHoZyRL6xkXmPJ&SrcJTitle=PROCEEDINGS+OF+THE+NATIONAL+ACADEMY+OF+SCIENCES+OF+THE+UNITED+STATES+OF+AMERICA&DestDOIRegistrantName=Proceedings+of+the+National+Academy+of+Sciences 
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| Author Notes: | Anna Katharina Schlusche, Sabine Ulrike Vay, Niklas Kleinenkuhnen, Steffi Sandke, Rafael Campos-Martin, Marta Florio, Wieland Huttner, Achim Tresch, Jochen Roeper, Maria Adele Rueger, Igor Jakovcevski, Malte Stockebrand, Dirk Isbrandt |
| Summary: | The development of the cerebral cortex relies on the controlled division of neural stem and progenitor cells. The requirement for precise spatiotemporal control of proliferation and cell fate places a high demand on the cell division machinery, and defective cell division can cause microcephaly and other brain malformations. Cell-extrinsic and-intrinsic factors govern the capacity of cortical progenitors to produce large numbers of neurons and glia within a short developmental time window. In particular, ion channels shape the intrinsic biophysical properties of precursor cells and neurons and control their membrane potential throughout the cell cycle. We found that hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits are expressed in mouse, rat, and human neural progenitors. Loss of HCN channel function in rat neural stem cells impaired their proliferation by affecting the cell-cycle progression, causing G1 accumulation and dysregulation of genes associated with human microcephaly. Transgene-mediated, dominant-negative loss of HCN channel function in the embryonic mouse telencephalon resulted in pronounced microcephaly. Together, our findings suggest a role for HCN channel subunits as a part of a general mechanism influencing cortical development in mammals. |
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| Item Description: | Gesehen am 22.03.2022 Published August 24, 2021 |
| Physical Description: | Online Resource |
| ISSN: | 1091-6490 |
| DOI: | 10.1073/pnas.2009393118 |