RT Journal Article
SR Electronic
T1 The Spinal Muscular Atrophy with Pontocerebellar Hypoplasia Gene <em>VRK1</em> Regulates Neuronal Migration through an Amyloid-β Precursor Protein-Dependent Mechanism
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 936
OP 942
DO 10.1523/JNEUROSCI.1998-14.2015
VO 35
IS 3
A1 Vinograd-Byk, Hadar
A1 Sapir, Tamar
A1 Cantarero, Lara
A1 Lazo, Pedro A.
A1 Zeligson, Sharon
A1 Lev, Dorit
A1 Lerman-Sagie, Tally
A1 Renbaum, Paul
A1 Reiner, Orly
A1 Levy-Lahad, Ephrat
YR 2015
UL http://www.jneurosci.org/content/35/3/936.abstract
AB 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.