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. VRK1 is a nuclear serine/threonine protein kinase known to 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.
['Vinograd-Byk|Hadar|H|', 'Sapir|Tamar|T|', 'Cantarero|Lara|L|', 'Lazo|Pedro A|PA|http://orcid.org/0000-0001-8997-3025', 'Zeligson|Sharon|S|', 'Lev|Dorit|D|http://orcid.org/0000-0001-6869-6727', 'Lerman-Sagie|Tally|T|', 'Renbaum|Paul|P|', 'Reiner|Orly|O|', 'Levy-Lahad|Ephrat|E|']
D016564:Amyloid beta-Protein Precursor D000818:Animals D002453:Cell Cycle D045744:Cell Line, Tumor D002465:Cell Movement D002526:Cerebellar Diseases D002531:Cerebellum D002540:Cerebral Cortex D002658:Developmental Disabilities D006801:Humans D047908:Intracellular Signaling Peptides and Proteins D008279:Magnetic Resonance Imaging D051379:Mice D009421:Nervous System Malformations D009474:Neurons D017346:Protein Serine-Threonine Kinases D014897:Spinal Muscular Atrophies of Childhood
VRK1 neuronal migration APP SMA-PCH (spinal muscular atrophy pontocerebellar hypoplasia)