{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T04:40:42Z","timestamp":1789706442196,"version":"4.0.1"},"reference-count":28,"publisher":"Society for Neuroscience","issue":"3","license":[{"start":{"date-parts":[[2015,7,21]],"date-time":"2015-07-21T00:00:00Z","timestamp":1437436800000},"content-version":"vor","delay-in-days":181,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2015,1,21]]},"abstract":"<jats:p>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 (<jats:italic>VRK1<\/jats:italic>), R358X, as a cause of SMA-PCH.<jats:italic>VRK1<\/jats:italic>-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<jats:italic>VRK1-<\/jats:italic>R358X homozygosity results in lack of VRK1 protein, and demonstrate a role for VRK1 in neuronal migration and neuronal stem cell proliferation. Using shRNA<jats:italic>in utero<\/jats:italic>electroporation in mice, we show that<jats:italic>Vrk1<\/jats:italic>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-\u03b2 precursor protein (<jats:italic>APP<\/jats:italic>), a known neuronal migration gene. APP overexpression rescues the phenotype caused by<jats:italic>Vrk1<\/jats:italic>knockdown, suggesting that VRK1 affects neuronal migration through an APP-dependent mechanism.<\/jats:p>","DOI":"10.1523\/jneurosci.1998-14.2015","type":"journal-article","created":{"date-parts":[[2015,1,21]],"date-time":"2015-01-21T19:18:29Z","timestamp":1421867909000},"page":"936-942","source":"Crossref","is-referenced-by-count":42,"title":["The Spinal Muscular Atrophy with Pontocerebellar Hypoplasia Gene<i>VRK1<\/i>Regulates Neuronal Migration through an Amyloid-\u03b2 Precursor Protein-Dependent 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