Essential role of the nuclear isoform of RBFOX1, a candidate gene for autism spectrum disorders, in the brain development

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.

Cell-type specialization in the brain is encoded by specific long-range chromatin topologies

“…The regulation of these long neuronal genes is further complicated by intricate splicing dynamics 50,51 , which require highly dynamic and adaptive responses based on neuronal activation state. It is therefore not surprising that for many of these long genes, including for Nrxn3, Rbfox1 and Nlgn1, genetic variants are often associated with or directly result in neuronal diseases [60][61][62] . Thus, understanding how genome folding relates with the response to environmental challenges is increasingly important to further our understanding of the mechanisms of neurological disease.…”

From rare Copy Number Variations to biological processes in ADHD

“…(62–65) Animal models have shown that RBFOX1 is involved in mouse corticogenesis and aggressive behaviours. (62,64,66,67) POLR3C is included in a well-known small CNV located at 1q21.1, which contributes to a broad spectrum of phenotypes in addition to ADHD, including morphological features and autism spectrum disorders (ASD). (68,69) Genes listed in Table 1 may be viewed as having, individually, the highest credibility as ADHD candidate genes.…”

Satellite-like cells contribute to pax7-dependent skeletal muscle repair in adult zebrafish

“…However, whether Rbfox2 is expressed in mouse satellite cells, and/or functions during skeletal muscle development, growth, and/or regeneration has not been studied. The closest murine Rbfox1l homolog, Rbfox1, is primarily studied as a regulator of neuronal splicing (Gehman et al, 2011; Hamada et al, 2016; O’Brien et al, 2012; Weyn-Vanhentenryck et al, 2015), but is also expressed in heart and skeletal muscle (Kalsotra et al, 2008; Kiehl et al, 2001; Underwood et al, 2005). Surprisingly, conditional and partial Rbfox1 depletion in satellite cells does not affect muscle regeneration, with the caveat that only ~70% knockdown was achieved (Pedrotti et al, 2015).…”