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

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Mavrovic , M , Uvarov , P , Delpire , E , Vutskits , L , Kaila , K & Puskarjov , M 2020 , ' Loss of non-canonical KCC2 functions promotes developmental apoptosis of cortical projection neurons ' , EMBO Reports , vol. 21 , no. 4 , 48880 . https://doi.org/10.15252/embr.201948880

Title: Loss of non-canonical KCC2 functions promotes developmental apoptosis of cortical projection neurons
Author: Mavrovic, Martina; Uvarov, Pavel; Delpire, Eric; Vutskits, Laszlo; Kaila, Kai; Puskarjov, Martin
Contributor: University of Helsinki, Molecular and Integrative Biosciences Research Programme
University of Helsinki, Molecular and Integrative Biosciences Research Programme
University of Helsinki, Molecular and Integrative Biosciences Research Programme
University of Helsinki, Molecular and Integrative Biosciences Research Programme
Date: 2020-04-03
Language: eng
Number of pages: 13
Belongs to series: EMBO Reports
ISSN: 1469-221X
URI: http://hdl.handle.net/10138/318336
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 GABA(A) 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 (KCC2(R952H)), 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.
Subject: CL-COTRANSPORTER KCC2
EXPRESSION
EXTRUSION
GABA
HIPPOCAMPAL-NEURONS
IN-VIVO
KCC2
MATURATION
NEURAL DEVELOPMENT
OHTAHARA SYNDROME
PROGRAMMED CELL-DEATH
cell death
chloride
cofilin
1182 Biochemistry, cell and molecular biology
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