Axon Guidance and Dendrite Arborization: Roles of Mammalian DSCAM and its Isoforms

Since DSCAM (Down Syndrome Cell Adhesion Molecule) was initially identified as a candidate gene for the neurological detects observed in Down Syndrome, it has emerged as a multi-faceted molecule integral to proper neurodevelopment. With a conserved domain structure among both vertebrates and invertebrates, DSCAM has been implicated in a wide range of neurodevelopment processes. Here we show that mammalian DSCAM can bind a classic axon guidance cue and mediate axon guidance. Additionally, we show that multiple DSCAM isoforms are dynamically regulated in different regions of the nervous system and most important we identified the first DSCAM isoforms that can mediate divergent functions.;Early in vitro studies highlighted DSCAM's ability to engage in homotypic binding intrans, but we show in Chapter 1, that DSCAM is also capable of binding Netrin-1 and is involved in the development of the mouse spinal cord. Through in vitro and in vivo experiments, we show that DSCAM functions independently and in collaboration with DCC to mediate the outgrowth and turning of commissural axons, respectively, towards the netrin-1 gradient emanating from ventral floor plate.;In Chapter 2, we explore DSCAM's protein expression pattern, primarily in the cerebellum and colliculus of wildtype mice. We then characterized a mutant DSCAM mouse line, DSCAMdel17 for potential phenotypes in these cerebral regions. We were surprised to discover the expression of multiple DSCAM proteins that are differentially expressed in different tissues and were not all affected in the mutant, suggesting the existence of alternatively spliced isoforms. Unlike the invertebrate counterpart, DSCAM in vertebrates have not been shown to have any functional isoforms. Our search for isoforms yielded new cytoplasmic domains that mediate different functions. These isoforms result from alternative splicing; the first includes an insertion of an extra exon and the other is a truncation resulting from retention of an intron.;This work reveals that mammalian DSCAM does indeed undergo alternative splicing and conceptually expands the possible roles for DSCAM in neurodevelopment. These combined studies have deepened our understanding of how mammalian DSCAM contributes to the development of a functional neural circuit. Furthermore, it has highlighted exciting avenues of research to be pursued in uncovering the full potential of DSCAM, a molecule that never tails to surprise with its ever-expanding repertoire of axon guidance capabilities.