The T-type Ca 2+ Channel Ca v 3.2 Regulates Differentiation of Neural Progenitor Cells during Cortical Development via Caspase-3

Neuroscience. 2019 Mar 15;402:78-89. doi: 10.1016/j.neuroscience.2019.01.015. Epub 2019 Jan 21.

Abstract

Here we report that the low-voltage-dependent T-type calcium (Ca2+) channel Cav3.2, encoded by the CACNA1H gene, regulates neuronal differentiation during early embryonic brain development through activating caspase-3. At the onset of neuronal differentiation, neural progenitor cells exhibited spontaneous Ca2+ activity. This activity strongly correlated with the upregulation of CACNA1H mRNA. Cells exhibiting robust spontaneous Ca2+ signaling had increased caspase-3 activity unrelated to apoptosis. Inhibition of Cav3.2 by drugs or viral CACNA1H knock down resulted in decreased caspase-3 activity followed by suppressed neurogenesis. In contrast, when CACNA1H was overexpressed, increased neurogenesis was detected. Cortical slices from Cacna1h knockout mice showed decreased spontaneous Ca2+ activity, a significantly lower protein level of cleaved caspase-3, and microanatomical abnormalities in the subventricular/ventricular and cortical plate zones when compared to their respective embryonic controls. In summary, we demonstrate a novel relationship between Cav3.2 and caspase-3 signaling that affects neurogenesis in the developing brain.

Keywords: Cacna1h; T-type calcium channels; caspase-3; neural differentiation; spontaneous Ca(2+) activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Channels, T-Type / genetics
  • Calcium Channels, T-Type / metabolism*
  • Calcium Signaling
  • Caspase 3 / metabolism*
  • Cell Differentiation*
  • Cerebral Cortex / growth & development*
  • Cerebral Cortex / metabolism*
  • Gene Expression Regulation, Developmental
  • Lateral Ventricles / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neural Stem Cells / metabolism*
  • Neuroepithelial Cells / metabolism

Substances

  • Cacna1h protein, mouse
  • Calcium Channels, T-Type
  • Caspase 3