Autism risk gene, A2BP1 plays an essential role in cortical development
Nanako Hamada, Hidenori Tabata, Hidenori Ito and Koh-ichi Nagata
Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Human Service Center
KAKENHI
A2BP1 (aka Fox1 or Rbfox1) is an RNA binding protein responsible for regulation of alternative splicing. Critical neurological functions for A2BP1 have been approved by human mutations in A2BP1 gene that cause neurodevelopmental disorders including autism spectrum disorder (ASD). To elucidate the pathophysiological relevance of A2BP1, we here performed cell biological analyses of neuron-specific isoforms (A016 and A030) of A2BP1 during cerebral development. Knockdown of A2BP1 isoforms by the in utero electroporation method caused neuronal positioning defects during corticogenesis. A2BP1 knockdown did not affect cell proliferation in the neural progenitor/stem cells. A016-deficient neurons showed bent and/or short leading process during radial migration. Time-lapse imaging then revealed that A016-deficient neurons could not be efficiently transformed to bipolar shape and exhibited abnormal shapes in the cortical plate (CP). As a result, migration of A016-deficient neurons was prevented in CP compared with control cells. Morphological defects were also observed in axonal growth. A016- or A030-silenced cortical neurons showed impaired axon elongation at P3, and innervation of axonal tips in the contralateral cortex diminished at P7. Taken together, deficiency in cortical neuronal migration and interhemispheric axonal growth may induce structural and functional defects of the cerebral cortex, leading to emergence of the clinical symptoms of neurodevelopmental disorders such as ASD.