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 two 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 have progressively become partially understood, downstream subcellular mechanisms and molecular machinery that implement precise and diverse 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 CPN associative projections, and that its deletion both strikingly reshapes these projections, and causes dramatic disruption to circuit-specific subcellular growth cone (GC) molecular machinery and social behavior and cognition in mice. CPN-specific embryonic deletion of Bcl11a causes loss of correct homotopic targeting in the contralateral cortex, re-routes a substantial proportion of their axonal projections through the evolutionarily older anterior commissure, and induces strikingly aberrant, but specific and precise, projections to the basolateral amygdala in adult mice. Importantly, bilateral deletion of Bcl11a from CPN alone results in abnormal social behavior and working memory. Mechanistically, we identify dysregulation of the CPN 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-specific associative circuitry formation, causing disease-related behavior.  Together, this work identifies critical functions for Bcl11a in CPN axonal connectivity, development of functional associative-social circuitry, 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, and the importance of understanding circuit-specific subcellular– e.g. soma vs. GC– localization of RNA and protein molecular machinery by neurons.