Effects of VRK1 deficiency on the neurophysiology and behavior of zebrafish

Vaccinia-related kinase 1 (VRK1) is a predominantly nuclear serine/threonine kinase implicated in nucleus disassembly and reassembly, cell cycle, and transcription regulation. VRK1 mutations in humans have been linked to several neurodegenerative diseases, including spinal muscular atrophy associated with microcephaly and impaired cognitive and motor function. Thus, it has been identified as potentially involved in the maintenance and development of the nervous system. However, precise pathophysiological mechanisms and VRK1 involvement in cognitive and motor dysfunction progression have yet to be thoroughly investigated. To elucidate the pathophysiological mechanisms underlying VRK1-related neurological disease, we established a vrk1-deficient (vrk1−/−) zebrafish and evaluated the neurological phenotype resulting from the mutation. We found growth retardation and microcephaly, characterized by reduced brain area with a reduced number of neuronal populations in the forebrain of the adult fish, associated with affected locomotor activity and low dopamine content, nuclear envelope formation defects, and heterochromatin formation in the brain. Furthermore, a significant reduction in neuronal progenitor cells in the vrk1−/− embryo suggests that vrk1 plays a role in neuronal development. We generated a complete null mutant model of Vrk1 in zebrafish and elucidated its neuronal effects in vivo, and our findings contribute to understanding the mechanism behind VRK1-related neurological diseases associated with microcephaly.