The C. elegans gene dig-1 encodes a giant member of the immunoglobulin superfamily that promotes fasciculation of neuronal processes

Abstract

The adhesion of growing neurites into appropriate bundles or fascicles is important for the development of correct synaptic connectivity in the nervous system. We describe fasciculation defects of animals with mutations in the C. elegans gene dig-1 and show that dig-1 encodes a giant molecule (13,100 amino acids) of the immunoglobulin superfamily. Five new alleles of dig-1 were isolated in a screen for mutations affecting the morphology or function of several classes of head sensory neurons. Mutants showed process defasciculation of several classes of neurons. Analysis of a temperature-sensitive allele revealed that dig-1 is required during embryogenesis for normal process fasciculation of one class of head sensory neuron. Partial sequencing of two alleles, RNA interference (RNAi) and rescuing experiments showed that dig-1 encodes a giant molecule of the immunoglobulin superfamily. DIG-1 protein contains many domains associated with adhesion, is likely secreted, and has some features of proteoglycans. dig-1 mutants were originally isolated due to their displaced gonads [Thomas, J.H., Stern, M.J., Horvitz, H.R., 1990. Cell interactions coordinate the development of the C. elegans egg-laying system. Cell 62, 1041-52]; thus, dig-1 alleles were also characterized for their effects on gonad placement. Mutant phenotypes suggest that DIG-1 may mediate cell movement as well as process fasciculation and that different regions of the protein may mediate these functions.

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

“…Three of 10 new Pva mutations proved to be alleles of dig-1, which encodes a putative extracellular matrix component previously reported to be involved in position maintenance of axons and neuronal cell bodies (Benard et al 2006;Burket et al 2006). Six other new Pva mutations were identified as alleles of anc-1, which encodes a member of the nesprin/ SYNE family of outer nuclear membrane proteins that link the cytoskeleton to the inner nuclear membrane (Starr and Fridolfsson 2010).…”

“…The locations of neuronal soma, axons, and dendrites must be maintained to ensure proper nervous system function during the addition and removal of neurons and synapses and in response to mechanical stresses associated with body growth and movement. The factors maintaining nervous system architecture are often distinct from those involved in its establishment during development, a division of labor which likely allows flexibility to cope with the stresses involved in remodeling, growth, and movement.The involvement of extracellular matrix components, cell adhesion molecules, and cytoskeletal proteins in previously reported neural maintenance activities demonstrate that adhesive cell-matrix and possibly cell-cell interactions play a critical role (Aurelio et al 2002;Bulow et al 2004;Sasakura et al 2005;Wang et al 2005;Benard et al 2006Burket et al 2006;Pocock et al 2008;Woo et al 2008; Zhou et al 2008). Although previously unreported, factors controlling nuclear position in neurons may also be predicted to play key roles in positional maintenance of neuronal soma.…”

“…The involvement of extracellular matrix components, cell adhesion molecules, and cytoskeletal proteins in previously reported neural maintenance activities demonstrate that adhesive cell-matrix and possibly cell-cell interactions play a critical role (Aurelio et al 2002;Bulow et al 2004;Sasakura et al 2005;Wang et al 2005;Benard et al 2006Burket et al 2006;Pocock et al 2008;Woo et al 2008; Zhou et al 2008). Although previously unreported, factors controlling nuclear position in neurons may also be predicted to play key roles in positional maintenance of neuronal soma.…”

“…We find that dgn-1 null mutants display a progressive displacement of lumbar neuron cell bodies, indicative of a defect in neuroanatomical maintenance. This neural role of dystroglycan likely involves interaction with extracellular partners, including the matrix component DIG-1 previously implicated in neural maintenance (Benard et al 2006;Burket et al 2006).…”

“…We find that dgn-1 null mutants display a progressive displacement of lumbar neuron cell bodies, indicative of a defect in neuroanatomical maintenance. This neural role of dystroglycan likely involves interaction with extracellular partners, including the matrix component DIG-1 previously implicated in neural maintenance (Benard et al 2006;Burket et al 2006).A forward genetic screen for other mutations producing dgn-1-like lumbar neuron maintenance defects identified a second novel maintenance factor: the KASH domain protein ANC-1, a nesprin/Syne protein known to mediate anchorage of nuclei and mitochondria Starr and Han 2002). Mutants in the KASH protein UNC-83 (Starr et al 2001) and in the ANC-1-and UNC-83-binding SUN domain protein UNC-84 (Malone et al 1999) also display lumbar maintenance defects, supporting the prediction that factors controlling nuclear position and migration are indeed critical in maintenance of neuron cell body location.…”