Functional antagonism of alpha-subunits of Kv channel in developing brain ventricular system

Abstract

The brain ventricular system is essential for neurogenesis and brain homeostasis. Its neuroepithelial lining effects these functions, but the underlying molecular pathways remain to be understood. We found that the K channels expressed in neuroepithelial cells determine formation of the ventricular system. The phenotype of a novel zebrafish mutant characterized by denudation of neuroepithelial lining of the ventricular system and hydrocephalus is mechanistically linked to Kcng4b, the homologue of the “silent” voltage-gated K channel alpha-subunit Kv6.4. We demonstrated that Kcng4b modulates proliferation of cells lining the ventricular system and maintains their integrity. The gain of Kcng4b function reduces brain ventricles. Electrophysiological studies supported an idea that Kcng4b mediates its effects via an antagonistic interaction with Kcnb1, the homologue of the electrically active delayed rectifier K channel subunit Kv2.1. The mutation of kcnb1 reduces the size of ventricular system and its gain of function causes hydrocephalus, i.e. opposite to the Kcng4b function. This demonstrates the dynamic interplay between K channel subunits in the neuroepithelium as a novel and critical regulator of ventricular development in the vertebrate brain.