Differential NOVA2-Mediated Splicing in Excitatory and Inhibitory Neurons Regulates Cortical Development and Cerebellar Function

Abstract

Highlights d cTag-CLIP provides a strategy to study cell-specific RNA regulation in vivo d NOVA2 controls unique RNA splicing programs in inhibitory and excitatory neurons d NOVA2 cTag-CLIP reveals a new mechanism of cell-specific AS regulation d NOVA2 regulates intron retention as a cis-acting scaffold for AS factor PTBP2

Chromatin-mediated alternative splicing regulates cocaine reward behavior

“…This computational data was further validated by the fact that the Srsf11 motifs identified in our dataset are also those most enriched by Srsf11 iCLIP (UCUCUC and CUCUCU) (Gonatopoulos-Pournatzis et al, 2018) ( Figure 4D). 7 additional splice motifs were enriched in our dataset, including neuro-oncological ventral antigen 2 (Nova2), polypyrimidine tract binding protein 2 (PTBP2) (Saito et al, 2019), but the enrichment patterns at splice junctions were highly similar to the permuted controls, indicating that those splice factors were not enriched at splice junctions of alternatively spliced genes in Set2 or cocaine SA datasets (Supplement figure 4C).…”

“…Alternative splicing is a key mechanism for gene regulation in brain. Neuron-specific isoform expression is essential to proper cell-type specification as shown from recent studies in neuronal development (Furlanis and Scheiffele, 2018;Saito et al, 2019;Schwartzentruber et al, 2018), disease (Gandal et al, 2018;de la Torre-Ubieta et al, 2016;Parikshak et al, 2016;Voineagu et al, 2011) and activity Parikshak et al, 2016;Quesnel-Vallières et al, 2016). While many neurological diseases, including autism (Quesnel-Vallières et al, 2016;Voineagu et al, 2011), Rett syndrome (Cheng et al, 2017;Kriaucionis and Bird, 2004;Li et al, 2016), Huntington's disease (Lin et al, 1993;Sathasivam et al, 2013;Wood, 2013), spinal muscular atrophy (Cartegni et al, 2006;Lorson et al, 1999;Parente and Corti, 2018;Xiong et al, 2015) and schizophrenia (Gandal et al, 2018;Glatt et al, 2011;Morikawa and Manabe, 2010;Nakata et al, 2009;Wu et al, 2012) have been linked to disruptions in alternative splicing, this mechanism of gene regulation is understudied in the context of drug abuse and addiction.…”

The gamma-Protocadherins regulate the survival of GABAergic interneurons during developmentally-regulated cell death

“…To investigate the role of the Pcdhgs in inhibitory neuron development, we used a pan-GABAergic Cre line to delete Pcdhg from broad classes of differentiating GABAergic cells. Conditional Pcdhg f mice (Lefebvre et al, 2008;Prasad et al, 2008) were crossed to Gad2-ires-Cre (Taniguchi, 2014;Taniguchi et al, 2011) which is active in the brain by late embryonic stages (Saito et al, 2019).…”

Approaches for measuring the dynamics of RNA–protein interactions

“…Another example of functional interaction between RBPs derived from CLIP maps comes from a comparative analysis of PTBP2–RNA interactions in the brain of wild type mice and mice lacking the RBP NOVA2 (Saito et al, ). Incorporating CLIP maps with splicing data from single and double knockouts of NOVA2 and PTBP2 showed that NOVA2 normally represses retention of distinct introns.…”