Highlights d PDI-1, a protein disulfide isomerase, regulates neuron migration d PDI-1 functions in EGL-20/Wnt-producing cells to control neuron migration d Protein disulfide isomerases are evolutionarily conserved regulators of Wnt secretion
Neuronal wiring during development requires that the growth cones of axons and dendrites are correctly guided to their appropriate targets. As in other animals, axon growth cones in Caenorhabditis elegans integrate information in their extracellular environment via interactions among transiently expressed cell surface receptors, their ligands, and the extracellular matrix (ECM). Components of the ECM undergo a wide variety of post-translational modifications that may affect efficacy of binding to neuronal guidance molecules. The most common modification of the ECM is prolyl 4-hydroxylation. However, little is known of its importance in the control of axon guidance. In a screen of prolyl 4-hydroxylase (P4H) mutants, we found that genetic removal of a specific P4H subunit, DPY-18, causes dramatic defects in C. elegans neuroanatomy. In dpy-18 mutant animals, the axons of specific ventral nerve cord neurons do not respect the ventral midline boundary and cross over to the contralateral axon fascicle. We found that these defects are independent of the known role of dpy-18 in regulating body size and that dpy-18 acts from multiple tissues to regulate axon guidance. Finally, we found that the neuronal defects in dpy-18 mutant animals are dependent on the expression of muscle-derived basement membrane collagens and motor neuron-derived ephrin ligands. Loss of dpy-18 causes dysregulated ephrin expression and this is at least partially responsible for the neurodevelopmental defects observed. Together, our data suggest that DPY-18 regulates ephrin expression to direct axon guidance, a role for P4Hs that may be conserved in higher organisms.
Nogo-A is a membrane-bound protein that functions to inhibit neuronal migration, adhesion, and neurite outgrowth during development. In the mature nervous system, Nogo-A stabilizes neuronal wiring to inhibit neuronal plasticity and regeneration after injury. Here, we show that RET-1, the sole Nogo-A homolog in Caenorhabditis elegans, is required to control developmental wiring of a specific subset of neurons. In ret-1 deletion mutant animals, specific ventral nerve cord axons are misguided where they fail to respect the ventral midline boundary. We found that ret-1 is expressed in multiple neurons during development, and, through mosaic analysis, showed that ret-1 controls axon guidance in a cell-autonomous manner. Finally, as in mammals, ret-1 regulates ephrin expression, and dysregulation of the ephrin ligand VAB-2 is partially responsible for the ret-1 mutant axonal defects. Together, our data present a previously unidentified function for RET-1 in the nervous system of C. elegans.
Highlights d PDI-1, a protein disulfide isomerase, regulates neuron migration d PDI-1 functions in EGL-20/Wnt-producing cells to control neuron migration d Protein disulfide isomerases are evolutionarily conserved regulators of Wnt secretion
Strains were grown using standard growth conditions on NGM agar at 20 0 C on Escherichia coli OP50, unless otherwise stated (Brenner, 1974).Neuroanatomical reporter strains used -mgIs70 Is ;LGIV zdIs13:Is . Detailed strain information is detailed in Table S2. Molecular cloning Ppdi-1::pdi-1 cDNA rescue constructThe Ppdi-1::pdi-1 cDNA rescue construct was generated by cloning the 841 bp pdi-1 promoter with SphI-SmaI into the pPD49.26 vector and then the pdi-1 cDNA using NheI-SacI. Pdpy-7::pdi-1 cDNA rescue constructThe Pdpy-7::pdi-1 cDNA rescue construct was generated by cloning pdi-1 cDNA with NheISacI into a dpy-7 expression vector. Pdpy-7::pdi-1 cDNA -HEEL rescue constructThe Pdpy-7::pdi-1 cDNA -HEEL rescue construct was generated using site-directed mutagenesis to remove the 12 nucleotides that encode HEEL at the C-terminus of the PDI-1 protein. Pegl-20::pdi-1 cDNA rescue constructThe Pegl-20::pdi-1 cDNA rescue construct was generated by cloning the 1910 bp egl-20 promoter with SphI-SmaI into the pPD49.26 vector containing the pdi-1 cDNA. Plin-44::pdi-1 cDNA rescue constructThe Plin-44::pdi-1 cDNA rescue construct was generated by cloning the 1150 bp lin-44 promoter with SphI-SmaI into the pPD49.26 vector containing the pdi-1 cDNA.
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