Tillman, D. E. | bioRxiv Science

bioRxiv2024

Bcl11b orchestrates subcerebral projection neuron axon development via cell-autonomous, non-cell-autonomous, and subcellular mechanisms

Both cell-intrinsic competency and extracellular cues regulate axon projection, but mechanisms that coordinate these elements remain poorly understood. Subcerebral projection neurons (SCPN) extend their primary axons from cortex through subcortical structures, including the striatum, targeting the brainstem and spinal cord. We identify that the transcription factor Bcl11b/Ctip2 functions in multiple independent neuron populations to control SCPN axon development. Bcl11b expressed by SCPN is required cell-autonomously for axonal outgrowth and efficient entry into the internal capsule within the striatum, while Bcl11b expressed by medium spiny neurons (MSN) non-cell-autonomously regulates SCPN axon fasciculation within the internal capsule and subsequent pathfinding. Further, integrated investigation of Bcl11b-null SCPN with transcriptomic, immunocytochemical, and in vivo growth cone purification approaches identifies that Cdh13 is localized along axons and on growth cone surfaces of SCPN in vivo, and mediates Bcl11b regulation of SCPN axonal outgrowth. Together, these results demonstrate that Bcl11b controls multiple aspects of SCPN axon development by coordinating intrinsic SCPN cell autonomous subcellular mechanisms and extrinsic MSN non-cell-autonomous mechanisms.

neuroscience↗

bioRxiv2022

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 (CPNSL) projections, and that its deletion strikingly re-routes some CPNSL projections subcortically, causes dramatic disruption to subcellular CPNSL growth cone (GC) molecular machinery, and disrupts social behavior and cognition in mice. CPNSL-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 CPNSL results in abnormal social behavior and working memory. Mechanistically, we identify dysregulation of the CPNSL 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 CPNSL circuitry formation. Together, this work identifies critical functions for Bcl11a in CPNSL 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 CPNSL, and the importance of understanding circuit-specific subcellular molecular machinery by neurons.

neuroscience↗