TY  - JOUR
AU  - Schlusche, Anna Katharina
AU  - Vay, Sabine Ulrike
AU  - Kleinenkuhnen, Niklas
AU  - Sandke, Steffi
AU  - Campos-Martín, Rafael
AU  - Florio, Marta
AU  - Huttner, Wieland
AU  - Tresch, Achim
AU  - Roeper, Jochen
AU  - Rueger, Maria Adele
AU  - Jakovcevski, Igor
AU  - Stockebrand, Malte
AU  - Isbrandt, Dirk
TI  - Developmental HCN channelopathy results in decreased neural progenitor proliferation and microcephaly in mice.
JO  - Proceedings of the National Academy of Sciences of the United States of America
VL  - 118
IS  - 35
SN  - 1091-6490
CY  - Washington, DC
PB  - National Acad. of Sciences
M1  - DZNE-2021-01470
SP  - e2009393118
PY  - 2021
AB  - 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.
KW  - Animals
KW  - Cell Cycle
KW  - Cell Death
KW  - Cell Proliferation: physiology
KW  - Cells, Cultured
KW  - Cerebral Cortex: cytology
KW  - Cerebral Cortex: embryology
KW  - Channelopathies: embryology
KW  - Channelopathies: etiology
KW  - Embryonic Stem Cells: metabolism
KW  - Embryonic Stem Cells: physiology
KW  - Humans
KW  - Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels: antagonists & inhibitors
KW  - Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels: genetics
KW  - Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels: metabolism
KW  - Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels: physiology
KW  - Mice
KW  - Mice, Transgenic
KW  - Microcephaly: embryology
KW  - Microcephaly: etiology
KW  - Neural Stem Cells: metabolism
KW  - Neural Stem Cells: physiology
KW  - Neurogenesis: physiology
KW  - Rats
KW  - HCN channelopathy (Other)
KW  - brain development (Other)
KW  - cell cycle (Other)
KW  - microcephaly (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:34429357
C2  - pmc:PMC8536352
DO  - DOI:10.1073/pnas.2009393118
UR  - https://pub.dzne.de/record/162815
ER  -