Neurons rely on dendrites for the acquisition of sensory and synaptic input from their particular receptive fields. Findings of aberrant dendritic morphology in disorders such as autism spectrum disorder (ASD) and schizophrenia highlight the importance of understanding how complex dendritic arbors are developed and maintained. During development, one of the goals of dendritic outgrowth is non-redundant coverage of a receptive field, which requires the avoidance of other dendrites both from the same neuron (self-avoidance) and from others (tiling). Tiling is evident in the organization of sensory neurites, such as those of C. elegans mechanosensory neurons, drosophila dendritic arborization (da) neurons, and vertebrate retinal ganglion cells. While tiling is a conserved property of many nervous systems, the molecular mechanisms by which it is established remain unclear. The goal of this project is to uncover the genetic and molecular mechanisms of dendritic tiling using the multi-dendritic FLP and PVD mechanosensory neurons of C. elegans as a model. The dendritic arbor of FLP covers the head of the worm while the arbor of PVD covers the body. While previous studies have identified both cell autonomous and cell non-autonomous cues for self-avoidance in outgrowing PVD dendrites, the mechanisms by which FLP and PVD establish distinct non-overlapping receptive fields remains unknown. From a pilot forward genetic screen, I have identified unc-33 as a gene required for the specification of FLP and PVD receptive field size. Unc-33 is a member of the Collapsin Response Mediator Protein (CRMP) family and is known to regulate axon development through the organization of microtubules. While the role of unc-33 in axon outgrowth is well-characterized, its role in dendritic tiling is unclear. In the first Aim of this project, I will use time-lapse imaging and cell ablation experiments to characterize the normal development of tiling between FLP and PVD neurons. In the second Aim of this project, I will use genetic and molecular techniques to determine the mechanism of action of unc-33 in regulating FLP and PVD tiling. In the third Aim of this project, I will use a combined candidate and forward genetic approach to identify novel regulators of tiling between FLP and PVD neurons. The results from this project will establish FLP and PVD as a new model for the study of dendritic tiling and identify novel pathways regulating this process. Understanding the basic mechanisms for the development for dendritic morphology will provide a foundation from which to understand how these mechanisms are altered in neurodevelopmental disorders.
Disorders such as Autism Spectrum Disorder (ASD) and schizophrenia are accompanied by characteristic defects in dendritic morphology, underscoring the importance of understanding the fundamental processes regulating the development of dendritic arbors. The goal of this project is to uncover the mechanisms by which dendrites specify non-overlapping receptive fields in a process known as tiling, which is a conserved property of dendritic arbors, using two mechanosensory neurons of the nematode Caenorhabditis elegans as a model. Results from this project will provide novel insight into the fundamental biological processes regulating the development of dendritic morphology and nervous system structure, which is a critical step in understanding the pathology of neurodevelopmental disorders.
