Temporal and Spatial Control of Neuronal Circuit Assembly and Maintenance

A schizophrenia-associated genetic variant in the 3′UTR of the human FURIN gene, a homolog of C. elegans kpc-1, underscores the importance of the 3′UTR in neuronal development. We elucidate how the kpc-1 plays a role in spatial control of neuronal circuit assembly. A secondary structural motif in the kpc-1 3′UTR is necessary to facilitate mRNA localization to branching points and promote local translation to promote dendrite self-avoidance. Overexpression of DMA-1, a receptor involved in dendrite development, mimics the branching and self-avoidance defects seen in kpc-1 mutants. Our findings suggest that local KPC-1 protein synthesis at branching points downregulates DMA-1, promoting proper dendritic architecture and self-avoidance in mechanosensory neurons critical for male courtship. In parallel, we investigate LIN-41, a tripartite motif (TRIM) protein, in regulating neuronal circuit maintenance. A congenital hydrocephalus-associated mutation in TRIM71, the human homolog of lin-41, causes precocious neuronal differentiation and early-onset dendrite degeneration in C. elegans. We show that this mutation leads to precocious neuronal differentiation, early-onset neurodegeneration, and behavioral abnormalities in adulthood. Cell type-specific knockdown and rescue experiments confirm that LIN-41 is essential during early neuronal development to prevent early-onset neurodegeneration. These findings highlight a potential link between developmental regulation and the onset of neurodegenerative conditions.