Extracellular matrix regulates UNC-6 (netrin) axon guidance by controlling the direction of intracellular UNC-40 (DCC) outgrowth activity.
How extracellular molecules influence the direction of axon guidance is poorly understood. The HSN axon of Caenorhabditis elegans is guided towards a ventral source of secreted UNC-6 (netrin). The axon's outgrowth response to UNC-6 is mediated by the UNC-40 (DCC) receptor. We have proposed that in response to the UNC-6 molecule the direction of UNC-40-mediated axon outgrowth is stochastically determined. The direction of guidance is controlled by asymmetric cues, including the gradient of UNC-6, that regulate the probability that UNC-40-mediated axon outgrowth is directed on average, over time, in a specific direction. Here we provide genetic evidence that a specialized extracellular matrix, which lies ventral to the HSN cell body, regulates the probability that UNC-40-mediated axon outgrowth will be directed ventrally towards the matrix. We show that mutations that disrupt the function of proteins associated with this matrix, UNC-52 (perlecan), UNC-112 (kindlin), VAB-19 (Kank), and UNC-97 (PINCH), decrease the probability of UNC-40-mediated axon outgrowth in the ventral direction, while increasing the probability of outgrowth in the anterior and posterior directions. Other results suggest that INA-1 (α integrin) and MIG-15 (NIK kinase) signaling mediate the response in HSN. Although the AVM axon also migrates through this matrix, the mutations have little effect on the direction of AVM axon outgrowth, indicating that responses to the matrix are cell-specific. Together, these results suggest that an extracellular matrix can regulate the direction of UNC-6 guidance by increasing the probability that UNC-40-mediated axon outgrowth activity will be oriented in a specific direction.
Department of Pathology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey, United States of America.
Yong
Y
Yang
Department of Pathology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey, United States of America.
Won Suk
WS
Lee
Department of Pathology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey, United States of America.
Xia
X
Tang
Department of Pathology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey, United States of America.
William G
WG
Wadsworth
D000818:Animals; D001369:Axons / Q000378:metabolism / Q000502:physiology*; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D003198:Computer Simulation; D003598:Cytoskeletal Proteins / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism*; D005822:Genetic Vectors / Q000235:genetics; D016023:Integrins / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D000075385:Netrins; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011509:Proteoglycans / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
D029742:Caenorhabditis elegans Proteins; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D017931:DNA Primers; C521951:Ina-1 protein, C elegans; D016023:Integrins; D008565:Membrane Proteins; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D000075385:Netrins; D011509:Proteoglycans; C411729:UNC-112 protein, C elegans; C102174:UNC-40 protein, C elegans; C078146:UNC-6 protein, C elegans; C117451:UNC-97 protein, C elegans; C480839:VAB-19 protein, C elegans; C082396:unc-52 protein, C elegans; C575831:Mig-15 protein, C elegans; D017346:Protein Serine-Threonine Kinases