UNC-5, a transmembrane protein with immunoglobulin and thrombospondin type 1 domains, guides cell and pioneer axon migrations in C. elegans

Leung-Hagesteijn, Chungyee; Spence, Andrew M.; Stern, Brian D.; Zhou, Youwen; Su, Mingwan; Hedgecock, Edward M.; Culotti, Joseph G.

doi:10.1016/0092-8674(92)90357-i

Cited by 383 publications

(211 citation statements)

References 63 publications

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“…The UNC5 receptor was initially identified in Caenorhabditis elegans as an axonal guidance transmembrane receptor (Leung-Hagesteijn et al, 1992) and, on the basis of a genetic screen, was predicted to interact with UNC6 (the C. elegans netrin-1 ortholog) (Hedgecock et al, 1990). Four homologs of UNC5 have been described in mammals (UNC5H1, 2, 3 and 4 in rodents and UNC5A, B, C and D in humans) (Leonardo et al, 1997).…”

Section: Dependence Receptors: a Short Historymentioning

confidence: 99%

Dependence receptors: a new paradigm in cell signaling and cancer therapy

2010

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Dependence receptors (DRs) now form a family of more than a dozen membrane receptors that are not linked by their structure, but by common functional traits. The most notable is their ability to trigger two opposite signaling pathways: in the presence of ligand, these receptors activate classic signaling pathways implicated in cell survival, migration and differentiation. In the absence of ligand, they do not stay inactive, rather they elicit an apoptotic signal. Thus, cells expressing this kind of receptor are dependent on the presence of ligand in the extracellular environment to survive. This review will recapitulate the increasing data regarding the molecular mechanisms associated with DRs, their potential implication during development, as well as their deregulation during tumorigenesis and, finally, their emergence as new possible therapeutic targets for cancer treatment.

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Section: Dependence Receptors: a Short Historymentioning

confidence: 99%

Dependence receptors: a new paradigm in cell signaling and cancer therapy

2010

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“…[21][22][23][24]. DCC/ UNC-40 seems to be required for both the attractive and repulsive responses, whereas UNC-5 is required only for repulsion [17][18][19][20]25,26 . Heterodimerization of UNC-40 with UNC-5 may convert UNC-40 from mediating attraction to repulsion 27 .…”

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confidence: 99%

Netrin requires focal adhesion kinase and Src family kinases for axon outgrowth and attraction

et al. 2004

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Although netrins are an important family of neuronal guidance proteins, intracellular mechanisms that mediate netrin function are not well understood. Here we show that netrin-1 induces tyrosine phosphorylation of proteins including focal adhesion kinase (FAK) and the Src family kinase Fyn. Blockers of Src family kinases inhibited FAK phosphorylation and axon outgrowth and attraction by netrin. Dominant-negative FAK and Fyn mutants inhibited the attractive turning response to netrin. Axon outgrowth and attraction induced by netrin-1 were significantly reduced in neurons lacking the FAK gene. Our results show the biochemical and functional links between netrin, a prototypical neuronal guidance cue, and FAK, a central player in intracellular signaling that is crucial for cell migration.Axon outgrowth and pathfinding are crucial for the formation of a normal nervous system. Extracellular cues that control these processes have been discovered in the past two decades. The netrin family of proteins can both promote axon outgrowth and guide the direction of axon pathfinding in many regions of the nervous system including the neocortex and the spinal cord 1-4 .In Caenorhabditis elegans, the gene unc-6 encodes the prototypical member of the netrin family 1,5 . In mammals, studies of commissural axons in the spinal cord showed a diffusible guidance activity in the floorplate 6 . The floorplate was able to promote the outgrowth of commissural axons and to attract them 7-10 . Biochemical purification of the axon-promoting activity from the chick brain led to the isolation of netrin-1, which was then shown to act as both a factor promoting axon outgrowth and a guidance cue to attract axons 2,3 . SequenceCorrespondence should be addressed to Y.R. (raoyi@pcg.wustl.edu). 6 These authors contributed equally to this work. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. NIH Public Access Author ManuscriptNat Neurosci. Author manuscript; available in PMC 2008 March 10. Published in final edited form as:Nat Neurosci. 2004 November ; 7(11): 1222-1232. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscriptsimilarities between UNC-6 and netrin-1 proteins established a remarkably conserved family of molecular cues in invertebrates and vertebrates 2,3,5,11-15 .The receptors for the netrins are 16,17 ) and in C. elegans, and their corresponding mammalian homologs are DCC (deleted in colorectal cancer), neogenin 19,20 and UNC5A-D (also known as . DCC/ UNC-40 seems to be required for both the attractive and repulsive responses, whereas UNC-5 is required only for repulsion [17][18][19][20]25,26 . Heterodimerization of UNC-40 with UNC-5 may convert UNC-40 from mediating attraction to repulsion 27 . There is also evidence, however, that DCC/UNC-40 can mediate repulsion in the absence of UNC-5 in specific cells in C. elegans 28 . In contrast to our knowledge of the multiple roles of netrins and their receptors, much less is known about intracellular signal transductio...

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“…In addition, netrins repel a subset of axons from the midline. Analysis of mutants lacking the function of genes encoding the netrins and netrin receptors have revealed a similar requirement for these factors in midline guidance in C. elegans (Hedgecock et al, 1990;Ishii et al, 1992;Leung-Hagesteijn et al, 1992), Drosophila Kolodziej et al, 1996;Mitchell et al, 1996;Keleman and Dickson, 2001), and mice Fazeli et al, 1997;Leonardo et al, 1997). In all three organisms, loss-of-function netrin mutants result in failure of commissural axons to be attracted to the midline as well as failure of a subset of projections to avoid the midline (Hedgecock et al, 1990;Harris et al, 1996;Mitchell et al, 1996;Serafini et al, 1996).…”

Section: Nervous System Wiringmentioning

confidence: 99%

“…Similarly, the attractive and repulsive effects of the Netrins are mediated by two distinct types of Netrin receptor in all three species. Netrin receptors most closely similar in amino acid sequence to the C. elegans Unc-40 receptor are required to mediate the attractive component of the Netrins (Hedgecock et al, 1990;Kolodziej et al, 1996;Fazeli et al, 1997) whereas receptors most similar to the C. elegans Unc-5 receptor are necessary in the subsets of axons that are repelled by the midline (Hedgecock et al, 1990;Leung-Hagesteijn et al, 1992;Leonardo et al, 1997;Keleman and Dickson, 2001).…”

Section: Nervous System Wiringmentioning

confidence: 99%