Aberrant dendrite morphologies have long been associated with neurodevelopmental and neuropsychiatric disorders, including Autism Spectrum Disorders and schizophrenia. Though many of these disorders show characteristic changes in dendrite development, there lacks a full understanding of the genes and mechanisms that regulate dendrite formation. To expand upon the knowledge of the genetic and molecular basis of dendrite development, this project will employ the use of C. elegans PVD neurons, in which mechanisms of development are known to be conserved. PVD neurons are multi-dendritic neurons that form characteristic candelabra-like arbors, and are polymodal nociceptors. Studies from our lab, and others, have shown that certain conserved extracellular adhesion molecules, including mnr-1/Menorin, sax-7/L1CAM, and dma-1/LRR transmembrane receptor, play a role in regulating dendritogenesis of PVD neurons. However, recent findings suggest that there may be more genes involved in PVD development. This project aims to characterize the phenotypic, genetic, and molecular functions of a novel conserved gene that reveals developmental defects in the C. elegans PVD neurons. To address the hypothesis that the novel signaling molecule works in concert with mnr-1, sax-7, and dma-1 to regulate PVD dendrite branching, experiments addressing the genetic, molecular, and phenotypic roles of the molecule will be performed. Experiments such as double mutant analyses, co-immunoprecipitation, and CRISPR/Cas9 genome editing will be executed to test genetic and physical interactions with mnr-1, sax-7, and dma-1. RNAi mediated knock-down experiments of candidate receptor genes, along with genetic crosses with mutant strains, will be performed to identity a putative receptor and piece together a mechanism of action. Together, these experiments will elucidate the role of a novel conserved signaling molecule in dendrite morphogenesis, helping to create a more complete understanding of the genes regulating neural growth during development and harboring potential for novel diagnoses.
Abnormal dendrite growth has been observed in many heritable neurological disorders, such as Autism Spectrum Disorders and schizophrenia. In this project, we aim to learn what role a poorly characterized gene encoding a secreted signaling molecule has in dendrite development. Understanding the genetic underpinnings of dendrite patterning may contribute to the diagnosis of and novel therapeutic approaches for disorders that result from irregular dendrite growth.
