Dynamic subtype- and context-specific subcellular RNA regulation in growth cones of developing neurons of the cerebral cortex

Abstract

Neurons of distinct subtypes compartmentalize subtype-specific function in part by differentially localizing and translating specific RNAs, but underlying mechanisms are not understood. Here we investigate messenger RNA localization and stability within subtype-specific growth cones (GCs), leading tips of growing axons, of long-range projection neurons (PNs) of the developing cerebral cortex. Comparison of GC-localized transcriptomes between two subtypes of PNs (interhemispheric-callosal and corticothalamic) across developmental stages identified both distinct and shared subcellular machinery involved in distinct phases of growth, target innervation and synaptogenesis, and enrichment of genes associated with neurodevelopmental and neuropsychiatric disorders. Further, we investigated sequence elements in dynamically GC-localized mRNAs, identifying GC-enriched motifs in 3' untranslated regions. For example, we identified that CPEB4, a translational regulator, regulates axonal branching and that RBMS1 functions dynamically in callosal circuit formation. This work offers generalizable insights for subcellular specialization in other polarized cells, toward elucidating neurodevelopmental and behavioral-cognitive disorders.