Abstract
Gene abnormalities in RBFOX1, encoding an mRNA-splicing factor, have been shown to cause autism spectrum disorder and other neurodevelopmental disorders. Since pathophysiological significance of the dominant nuclear isoform in neurons, RBFOX1-isoform1 (iso1), remains to be elucidated, we performed comprehensive analyses of Rbfox1-iso1 during mouse corticogenesis. Knockdown of Rbfox1-iso1 by in utero electroporation caused abnormal neuronal positioning during corticogenesis, which was attributed to impaired migration. The defects were found to occur during radial migration and terminal translocation, perhaps due to impaired nucleokinesis. Axon extension and dendritic arborization were also suppressed in vivo in Rbfox1-iso1-deficient cortical neurons. In addition, electrophysiology experiments revealed significant defects in the membrane and synaptic properties of the deficient neurons. Aberrant morphology was further confirmed by in vitro analyses; Rbfox1-iso1-konckdown in hippocampal neurons resulted in the reduction of primary axon length, total length of dendrites, spine density and mature spine number. Taken together, this study shows that Rbfox1-iso1 plays an important role in neuronal migration and synapse network formation during corticogenesis. Defects in these critical processes may induce structural and functional defects in cortical neurons, and consequently contribute to the pathophysiology of neurodevelopmental disorders with RBFOX1 abnormalities.
Highlights
By RBFOX1 abnormalities may underlie the clinical outcome of the aforementioned disorders, unidentified modifiers might contribute to their clinical complexity
Since neuronal migration is essential for corticogenesis, we examined the role of Rbfox1-iso[1] in the migration of newly generated cortical neurons by RNAi experiments
We examined if Rbfox[2] and Rbfox[3] are implicated in the cortical neuron positioning since these proteins are highly homologous to Rbfox1. pSuper-mRbfox[2] and –mRbfox[3] efficiently knocked down mRbfox[2] and mRbfox[3], respectively, in COS7 cells (Fig. 4a)
Summary
By RBFOX1 abnormalities may underlie the clinical outcome of the aforementioned disorders, unidentified modifiers might contribute to their clinical complexity. To better understand the pathophysiological basis of ASD and other neurodevelopmental disorders, elucidating the physiological function(s) of RBFOX1 in the cortical development is essential. While we have recently analyzed the pathophysiological relevance of the minor neuronal cytoplasmic isoform, Rbfox1-isoform[5] (A2BP1-A030), which was referred to as Rbfox1-iso[222], the pathophysiological significance of the dominant neuronal nuclear isoform, Rbfox1-isoform[1] (A2BP1-A016; Rbfox1-iso1), remains to be clarified. We here carried out comprehensive analyses of Rbfox1-iso[1] to elucidate its role in neurodevelopmental disorders
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