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Loss of non‐canonical KCC 2 functions promotes developmental apoptosis of cortical projection neurons
Author(s) -
Mavrovic Martina,
Uvarov Pavel,
Delpire Eric,
Vutskits Laszlo,
Kaila Kai,
Puskarjov Martin
Publication year - 2020
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201948880
Subject(s) - apoptosis , microbiology and biotechnology , cortical neurons , biology , projection (relational algebra) , neuroscience , computer science , genetics , algorithm
KCC 2, encoded in humans by the SLC 12A5 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, KCC 2 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 KCC 2 at non‐significant levels, here we show that loss of KCC 2 enhances apoptosis of late‐born upper‐layer cortical projection neurons in the embryonic brain. In utero electroporation of plasmids encoding truncated, transport‐dead KCC 2 constructs retaining the CTD was as efficient as of that encoding full‐length KCC 2 in preventing elimination of migrating projection neurons upon conditional deletion of KCC 2. This was in contrast to the effect of a full‐length KCC 2 construct bearing a CTD missense mutation ( KCC 2 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 KCC 2 in migrating cortical projection neurons.