C. elegans dystroglycan coordinates responsiveness of follower axons to dorsal/ventral and anterior/posterior guidance cues

Abstract

Neural development in metazoans is characterized by the establishment of initial process tracts by pioneer axons and the subsequent extension of follower axons along these pioneer processes. Mechanisms governing the fidelity of follower extension along pioneered routes are largely unknown. In C. elegans, formation of the right angle-shaped lumbar commissure connecting the lumbar and preanal ganglia is an example of pioneer/follower dynamics. We find that the dystroglycan ortholog DGN-1 mediates the fidelity of follower lumbar commissure axon extension along the pioneer axon route. In dgn-1 mutants, the axon of the pioneer PVQ neuron faithfully establishes the lumbar commissure, but axons of follower lumbar neurons, such as PVC, frequently bypass the lumbar commissure and extend along an oblique trajectory directly toward the preanal ganglion. In contrast, disruption of the UNC-6/netrin guidance pathway principally perturbs PVQ ventral guidance to pioneer the lumbar commissure. Loss of DGN-1 in unc-6 mutants has a quantitatively similar effect on follower axon guidance regardless of PVQ axon route, indicating that DGN-1 does not mediate follower/pioneer adhesion. Instead, DGN-1 appears to block premature responsiveness of follower axons to a preanal ganglion-directed guidance cue which mediates ventral-to-anterior reorientation of lumbar commissure axons. Deletion analysis shows that only the most N-terminal DGN-1 domain is required for these activities. These studies suggest that dystroglycan modulation of growth cone responsiveness to conflicting guidance cues is important for restricting follower axon extension to the tracts laid down by pioneers.

Neural Maintenance Roles for the Matrix Receptor Dystroglycan and the Nuclear Anchorage Complex in Caenorhabditis elegans

“…Neural expression of dgn-1 subsides after the L1 stage, with the exception of the PVP neurons in the preanal ganglion Johnson and Kramer, 2012). We reexpressed dgn-1(+) in dgn-1 null animals from transgenes under the control of various tissue-restricted heterologous gene control regions ("promoters") to determine the site of DGN-1 function in lumbar neuron maintenance (references in Materials and Methods).…”

“…We recently reported that dgn-1(cg121) animals display an axon guidance defect of follower lumbar commissure axons descending from neurons of the lumbar ganglion, in which follower axons frequently fail to extend into the preanal ganglion via the lumbar commissure and instead extend along a oblique trajectory directly toward the preanal ganglion (Johnson and Kramer 2012). This lumbar axon guidance defect appears to be an independent phenotype of dgn-1(cg121) for several reasons.…”

“…A common feature of these previously identified maintenance factors is that they potentially mediate cell-cell or cell-matrix interactions. Current models of the role of these maintenance factors in stabilizing neuronal soma and neurite position emphasize their possible function in contributing to cell-matrix attachment .DGN-1 function may be required only for a critical period during embryogenesis to establish a maintenance pathway that continues to protect PVQ and other lumbar neurons from displacement throughout development, on the basis of the findings that early embryonic but not later embryonic neural expression of DGN-1 rescues PVQ mispositioning in dgn-1 null mutants (this report) and that dgn-1 is expressed in neurons (including the lumbar ganglion neurons) only transiently during embryonic development, with the exception of the PVP neurons in the preanal ganglion Johnson and Kramer 2012). An intriguing possibility is that DGN-1 interaction with the matrix modulates some aspect of neural differentiation that establishes a critical maintenance program early in postmitotic neurons.…”

“…A role for dystroglycan-matrix interactions in aspects of cell differentiation is not unprecedented. Dystroglycan is required for robust response of mammary epithelial cells to prolactin or growth hormone (Leonoudakis et al 2010) and modulates insulin-like growth factor 1 signaling during oligodendrocyte differentiation (Galvin et al 2010).We recently reported that dgn-1(cg121) animals display an axon guidance defect of follower lumbar commissure axons descending from neurons of the lumbar ganglion, in which follower axons frequently fail to extend into the preanal ganglion via the lumbar commissure and instead extend along a oblique trajectory directly toward the preanal ganglion (Johnson and Kramer 2012). This lumbar axon guidance defect appears to be an independent phenotype of dgn-1(cg121) for several reasons.…”

“…Dystroglycan is expressed in neurons throughout the mouse brain (Zaccaria et al 2001), where it has no significant role in histogenesis but is important in synaptic function, e.g., during long-term potentiation in the hippocampus (Moore et al 2002;Satz et al 2010). In C. elegans, the dystroglycan ortholog DGN-1 is not present in muscle but is expressed in epithelia and neurons and is involved in epithelial morphogenesis and neural guidance Johnson and Kramer 2012). We find that dgn-1 null mutants display a progressive displacement of lumbar neuron cell bodies, indicative of a defect in neuroanatomical maintenance.…”