Send to

Choose Destination
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

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


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.


GABA ; KCC2; cell death; chloride; cofilin


Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center