The spinal muscular atrophy with pontocerebellar hypoplasia gene VRK1 regulates neuronal migration through an amyloid-β precursor protein-dependent mechanism

Spinal muscular atrophy with pontocerebellar hypoplasia (SMA-PCH) is an infantile SMA variant with additional manifestations, particularly severe microcephaly. We previously identified a nonsense mutation in Vaccinia-related kinase 1 (VRK1), R358X, as a cause of SMA-PCH. VRK1-R358X is a rare founder mutation in Ashkenazi Jews, and additional mutations in patients of different origins have recently been identified.VRK1is a nuclear serine/threonine protein kinaseknownto play multiple roles in cellular proliferation, cell cycle regulation, and carcinogenesis. However, VRK1 was not known to have neuronal functions before its identification as a gene mutated in SMA-PCH. Here we show that VRK1-R358X homozygosity results in lack of VRK1 protein, and demonstrate a role for VRK1 in neuronal migration and neuronal stem cell proliferation. Using shRNA in utero electroporation in mice, we show that Vrk1 knockdown significantly impairs cortical neuronal migration, and affects the cell cycle of neuronal progenitors. Expression of wild-type human VRK1 rescues both proliferation and migration phenotypes. However, kinase-dead human VRK1 rescues only the migration impairment, suggesting the role of VRK1 in neuronal migration is partly noncatalytic. Furthermore, we found that VRK1 deficiency in human and mouse leads to downregulation of amyloid-β precursor protein (APP), a known neuronal migration gene. APP overexpression rescues the phenotype caused by Vrk1 knockdown, suggesting that VRK1 affects neuronal migration through an APP-dependent mechanism.This study was supported by grants from the Israel Science Foundation (Grant 702/13 to P.R. and E.L.-L., and Grant 47/10 and 322/13 to O.R. and T.S.); by the Minerva Foundation with funding from the Federal German Ministry for Education and Research, the Jérôme Lejeune Foundation, the Benoziyo Center for Neurological diseases, the Kekst Family Center for Medical Genetics, and the David and Fela Shapell Family Center for Genetic Disorders Research (to O.R.); by the JAE (Programa Junta para la Amplición de Estudios) Consejo Superior de Investigaciones Científicas Fondo Social Europeo fellowship (to L.C.); by the Ministerio de Educación, Ciencia e Innovación (SAF2010-14935 and SAF2013-44810R, to P.A.L.); and by Kutxa-Fundación Inbiomed (to P.A.L.).Peer Reviewe