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EMBO Rep. 2020 Apr 3;21(4):e48880. doi: 10.15252/embr.201948880. Epub 2020 Feb 17.

Loss of non-canonical KCC2 functions promotes developmental apoptosis of cortical projection neurons.

Author information

1
Molecular and Integrative Biosciences, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
2
Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
3
Department of Anesthesiology, Vanderbilt University, Nashville, TN, USA.
4
Department of Basic Neurosciences, University of Geneva Medical School, Geneva 4, Switzerland.
5
Department of Anesthesiology, Pharmacology, Intensive Care and Emergency Medicine, University Hospitals of Geneva, Geneva 4, Switzerland.
#
Contributed equally

Abstract

KCC2, encoded in humans by the SLC12A5 gene, is a multifunctional neuron-specific protein initially identified as the chloride (Cl- ) extruder critical for hyperpolarizing GABAA receptor currents. Independently of its canonical function as a K-Cl cotransporter, KCC2 regulates the actin cytoskeleton via molecular interactions mediated through its large intracellular C-terminal domain (CTD). Contrary to the common assumption that embryonic neocortical projection neurons express KCC2 at non-significant levels, here we show that loss of KCC2 enhances apoptosis of late-born upper-layer cortical projection neurons in the embryonic brain. In utero electroporation of plasmids encoding truncated, transport-dead KCC2 constructs retaining the CTD was as efficient as of that encoding full-length KCC2 in preventing elimination of migrating projection neurons upon conditional deletion of KCC2. This was in contrast to the effect of a full-length KCC2 construct bearing a CTD missense mutation (KCC2R952H ), which disrupts cytoskeletal interactions and has been found in patients with neurological and psychiatric disorders, notably seizures and epilepsy. Together, our findings indicate ion transport-independent, CTD-mediated regulation of developmental apoptosis by KCC2 in migrating cortical projection neurons.

KEYWORDS:

GABA ; KCC2; cell death; chloride; cofilin

PMID:
32064760
DOI:
10.15252/embr.201948880

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