Loss of non‐canonical KCC2 functions promotes developmental apoptosis of cortical projection neurons. (17th February 2020)

• Record Type: Journal Article
• Authors: Mavrovic, Martina; Uvarov, Pavel; Delpire, Eric; Vutskits, Laszlo; Kaila, Kai; Puskarjov, Martin
• Is Part Of: EMBO reports. Volume 21:Number 4(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-02-17
• Subjects: cell death -- chloride -- cofilin -- GABA -- KCC2; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201948880
• Languages: English
• ISSNs: 1469-221X

Abstract

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 (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. Synopsis: The K‐Cl co‐transporter KCC2 is expressed in migrating late‐born upper layer cortical projection neurons, and it is necessary to promote their survival during the first major wave of apoptosis in the neocortex. This effect is independent of the KCC2 ion co‐transport function. Deletion of KCC2 from late‐born upper cortical layer projection neurons increases their apoptosis in embryonic mice. Neuronal survival was rescued by constructs encoding Cl − transport‐dead KCC2. The intracellular C‐terminal domain of KCC2 was sufficient to prevent neuronal loss. A disease variant of KCC2 with a missense mutation in the C‐terminal domain, found in neuropsychiatric patients, was unable to rescue survival of projection neurons. Abstract : The K‐Cl co‐transporter KCC2 promotes the survival of late‐born upper layer cortical projection neurons during the first major wave of apoptosis in the mouse neocortex. This effect is independent of the KCC2 ion co‐transport function.