Date of Award
Summer 6-30-2015
Degree Type
Thesis
Degree Name
Master of Science in Integrative Biology (MSIB)
Department
Biology
Committee Chair/First Advisor
Johnathan L. McMurry
Major Professor
Martin L. Hudson
Second Committee Member
Susan M.E. Smith
Third Committee Member
Scott J. Nowak
Abstract
Eph receptor tyrosine kinases and their ephrin ligands are required for multiple aspects of nervous system development including axon outgrowth, synaptic plasticity, and the formation of topographic maps in the visual system. The Caenorhabditis elegans ephrin-A, efn-4, has a defined role in hypodermal patterning but its role in nervous system development is not well understood. We find that loss-of-function mutations in efn-4 lead to suppression of axon branching in C. elegans model of X-linked Kallmann syndrome, a human genetic disorder that presents with loss of sense of smell and failure to undergo spontaneous puberty. In addition, efn-4 mutants have defects in AIY interneuron axon outgrowth. Tissue specific rescue experiments indicate that efn-4 is required non-cell autonomously in the hypodermis to promote axon extension. Also, non-cell autonomous expression in the body wall muscle is sufficient to rescue anosmin-dependent axon branching, suggesting that primary axon outgrowth is genetically distinct from axon branching. Previous genetic and biochemical analyses failed to establish whether the canonical C. elegans Eph receptor, vab-1, functions as the efn-4 receptor during embryonic development. We show via biolayer interferometry that VAB-1 binds with high-affinity to EFN-4. Furthermore, EFN-4 binds with promiscuity to both the canoncial VAB-1 Eph receptor in C. elegans and additionally to at least one other binding partner the L1CAM (L1 Cell Adhesion Molecule) LAD-2. VAB-1 may have additional functional roles in guiding AIY primary neurite outgrowth to the central plexus. Our findings suggest EFN-4 is a key player in cell-to-cell communications that guide AIY neuronal projections.