Schlusche, Anna Katharina, Vay, Sabine Ulrike ORCID: 0000-0002-3289-7807, Kleinenkuhnen, Niklas, Sandke, Steffi, Campos-Martin, Rafael ORCID: 0000-0002-1395-8571, Florio, Marta, Huttner, Wieland, Tresch, Achim ORCID: 0000-0002-4146-6371, Roeper, Jochen, Rueger, Maria Adele, Jakovcevski, Igor, Stockebrand, Malte and Isbrandt, Dirk ORCID: 0000-0002-4720-1016 (2021). Developmental HCN channelopathy results in decreased neural progenitor proliferation and microcephaly in mice. Proc. Natl. Acad. Sci. U. S. A., 118 (35). WASHINGTON: NATL ACAD SCIENCES. ISSN 1091-6490

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Schlusche, Anna KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vay, Sabine UlrikeUNSPECIFIEDorcid.org/0000-0002-3289-7807UNSPECIFIED
Kleinenkuhnen, NiklasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sandke, SteffiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Campos-Martin, RafaelUNSPECIFIEDorcid.org/0000-0002-1395-8571UNSPECIFIED
Florio, MartaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huttner, WielandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tresch, AchimUNSPECIFIEDorcid.org/0000-0002-4146-6371UNSPECIFIED
Roeper, JochenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rueger, Maria AdeleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jakovcevski, IgorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stockebrand, MalteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Isbrandt, DirkUNSPECIFIEDorcid.org/0000-0002-4720-1016UNSPECIFIED
URN: urn:nbn:de:hbz:38-599064
DOI: 10.1073/pnas.2009393118
Journal or Publication Title: Proc. Natl. Acad. Sci. U. S. A.
Volume: 118
Number: 35
Date: 2021
Publisher: NATL ACAD SCIENCES
Place of Publication: WASHINGTON
ISSN: 1091-6490
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ION CHANNELS; REGULATED EXPRESSION; CELL-PROLIFERATION; H-CHANNELS; STEM; NEURONS; GENE; VOLTAGE; CURRENTS; EXCITABILITYMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/59906

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