MADD-4 is a secreted cue required for midline-oriented guidance in Caenorhabditis elegans.
The netrins and slits are two families of widely conserved cues that guide axons and cells along the dorsal-ventral (D-V) axis of animals. These cues typically emanate from the dorsal or ventral midlines and provide spatial information to migrating cells by forming gradients along the D-V axis. Some cell types, however, extend processes to both the dorsal and ventral midlines, suggesting the existence of additional guidance cues that are secreted from both midlines. Here, we report that a previously uncharacterized protein called MADD-4 is secreted by the dorsal and ventral nerve cords of the nematode C. elegans to attract sensory axons and muscle membrane extensions called muscle arms. MADD-4's activity is dependent on UNC-40/DCC, a netrin receptor, which functions cell-autonomously to direct membrane extension. The biological role of MADD-4 orthologs, including ADAMTSL1 and 3 in mammals, is unknown. MADD-4 may therefore represent the founding member of a family of guidance proteins.
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Ashwin
A
Seetharaman
Guillermo
G
Selman
Rachel
R
Puckrin
Louis
L
Barbier
Eric
E
Wong
Serena A
SA
D'Souza
Peter J
PJ
Roy
D000071096:ADAMTS Proteins; D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002465:Cell Movement; D003463:Cues; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism*; D009132:Muscles / Q000166:cytology / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009417:Nerve Tissue / Q000166:cytology / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D000075386:Netrin Receptors; D011401:Promoter Regions, Genetic / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism
C454120:ADAMTSL1 protein, human; C491337:ADAMTSL3 protein, human; D029742:Caenorhabditis elegans Proteins; D015815:Cell Adhesion Molecules; D016326:Extracellular Matrix Proteins; D020662:Guanine Nucleotide Exchange Factors; C568399:MADD-4 protein, C elegans; D009419:Nerve Tissue Proteins; D000075386:Netrin Receptors; D011956:Receptors, Cell Surface; C102174:UNC-40 protein, C elegans; D000071096:ADAMTS Proteins