ASD gene Bcl11a regulates subcellular RNA localization, associative circuitry, and social behavior

Precise, area-specific connectivity of interhemispheric callosal projection neurons (CPN) in the cerebral cortex is critical for sensory, associative, and behavioral functions. CPN circuitry, which connects and integrates the cerebral hemispheres via the corpus callosum, is centrally implicated in autism spectrum disorder (ASD) and intellectual disability (ID). Though transcriptional controls regulating CPN subtype and areal development are partially understood, downstream subcellular molecular machinery that implements CPN circuitry is essentially unknown. Here, we identify that the highly penetrant ASD/ID risk gene Bcl11a/Ctip1 is critical developmentally for appropriate and precise areal targeting of superficial layer CPN (CPN SL ) projections, and that its deletion strikingly re-routes some CPN SL projections subcortically, causes dramatic disruption to subcellular CPN SL growth cone (GC) molecular machinery, and disrupts social behavior and cognition in mice. CPN SL -specific embryonic deletion of Bcl11a causes loss of correct homotopic targeting in the contralateral cortex, re-routes a substantial proportion of axonal projections through the anterior commissure, and induces strikingly aberrant, but specific and precise, projections to the basolateral amygdala. Importantly, bilateral deletion of Bcl11a from CPN SL results in abnormal social behavior and working memory. Mechanistically, we identify dysregulation of the CPN SL axonal GC-localized transcriptome in Bcl11a nulls, due to either aberrant transcription or trafficking of individual transcripts. These molecular mis-localizations disrupt axon guidance and CPN SL circuitry formation. Together, this work identifies critical functions for Bcl11a in CPN SL axonal connectivity, development of functional associative-social circuitry, and regulation of subtype-specific subcellular molecular machinery in vivo , revealing novel GC-localized transcripts that regulate precise axonal targeting and circuit formation. These results elucidate development and ASD/ID disease-related circuit disruption of CPN SL , and the importance of understanding circuit-specific subcellular molecular machinery by neurons.