Sequestration of growth cone surface proteins by cytoplasmic Lrrtm2 induces de novo amygdala innervation by cerebral cortex associative neurons

Precise establishment of distinct cerebral cortex circuits is essential for sensorimotor function, high-level cognition, and cross-modality integration and association. Although an increasing set of molecular controls over subtype-specific cortical wiring have been identified, much less is known about how molecules in growth cones (GCs) regulate precise long-range projection of axons through complex environments, or how dysregulation of GC molecular machinery disrupts precision of circuit formation. Here, we discover a generalizable mechanism for regulation of precise circuit wiring by focusing on callosal projection neurons (CPN), which link cortical hemispheres via the corpus callosum. CPN are centrally involved in associative and cognitive function, and are often disrupted in people with autism spectrum disorders (ASD) and intellectual disabilities (ID). We identify dysregulated subcellular CPN GC proteomes in vivo after CPN-specific deletion of Bcl11a / Ctip1 , a transcription factor (TF) with variants that cause ASD/ID in humans, and validate localization of dysregulated proteins to CPN GCs ex vivo . We identify that disruption of Lrrtm2 – a canonically postsynaptic transmembrane protein – in CPN GCs specifically induces de novo innervation of the amygdala, an evolutionarily ancient regulator of social behavior, cognition, and anxiety that is abnormally activated in humans with ASD. Mechanistically, we identify that deletion of Bcl11a from CPN disrupts targeting of Lrrtm2 to CPN GC membranes, causing cytoplasmic sequestration of key CPN GC surface proteins, and resulting in aberrant innervation of basolateral amygdala (BLA), which is typically targeted by evolutionarily older archicortex. Together, this work connects deletion of a causal ASD/ID TF, dysregulation of a non-canonical control over GC surface protein remodeling, and formation of a de novo , subtype-specific circuit between cerebral cortex and BLA – similar mechanisms likely generalize across neuron subtypes. These results expand conceptual understanding of how diverse circuits are precisely constructed and potentially evolve, and how coordinated dysregulation of GC molecules can disrupt precise subtype-specific circuitry, contributing to diverse neurodevelopmental and neuropsychiatric disorders.