Neuronal post-developmentally acting SAX-7S/L1CAM can function as cleaved fragments to maintain neuronal architecture inC. elegans

Abstract

ABSTRACTWhereas remarkable advances have uncovered mechanisms that drive nervous system assembly, the processes responsible for the lifelong maintenance of nervous system architecture remain poorly understood. Subsequent to its establishment during embryogenesis, neuronal architecture is maintained throughout life in the face of the animal’s growth, maturation processes, the addition of new neurons, body movements, and aging. TheC. elegansprotein SAX-7, homologous to the vertebrate L1 protein family, is required for maintaining the organization of neuronal ganglia and fascicles after their successful initial embryonic development. To dissect the function ofsax-7in neuronal maintenance, we generated a null allele andsax-7S-isoform-specific alleles. We find that the nullsax-7(qv30)is, in some contexts, more severe than previously described mutant alleles, and that the loss ofsax-7Slargely phenocopies the null, consistent withsax-7Sbeing the key isoform in neuronal maintenance. Using a sfGFP::SAX-7S knock-in, we observesax-7Sto be predominantly expressed across the nervous system, from embryogenesis to adulthood. Yet, its role in maintaining neuronal organization is ensured by post-developmentally acting SAX-7S, as larval transgenicsax-7S(+) expression alone is sufficient to profoundly rescue the null mutants’ neuronal maintenance defects. Moreover, the majority of the protein SAX-7 appears to be cleaved, and we show that these cleaved SAX-7S fragments together, not individually, can fully support neuronal maintenance. These findings contribute to our understanding of the role of the conserved protein SAX-7/L1CAM in long-term neuronal maintenance, and may help decipher processes that go awry in some neurodegenerative conditions.