Expression of the UNC-5 guidance receptor in the touch neurons of C. elegans steers their axons dorsally

Hamelin, Michel; Zhou, Youwen; Su, Mingwan; Scott, Ian M.; Culotti, Joseph G.

doi:10.1038/364327a0

Cited by 225 publications

(116 citation statements)

References 16 publications

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“…Netrins are expressed by the CNS midline cells and are secreted into the extracellular space, where they presumably form a gradient that guides commissural growth cones toward the CNS midline Serafini et al, 1994). In netrin mutants no attractive signal is generated and the majority of axons fails to cross the midline in the first place (Hamelin et al, 1993;Harris et al, 1996;Hedgecock et al, 1990;Mitchell et al, 1996;Serafini et al, 1996). A similar mutant phenotype is displayed by animals lacking the Netrin receptor Unc40/Dcc/Fra (Fazeli et al, 1997;Keino-Masu et al, 1996;Kolodziej et al, 1996).…”

Section: Introductionmentioning

confidence: 79%

TheDrosophilaARF6-GEF Schizo controls commissure formation by regulating Slit

2004

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The CNS of bilateral symmetric organisms is characterized by intensive contralateral axonal connections. Genetic screens in Drosophila have identified only a few genes required for guiding commissural growth cones toward and across the midline. Two evolutionarily conserved signaling molecules, Netrin and Slit, are expressed in the CNS midline cells. Netrin acts primarily as an attractive signaling cue, whereas Slit mediates repulsive functions. Here, we describe a detailed analysis of the Drosophilagene schizo, which is required for commissure formation. schizo leads to a commissural phenotype reminiscent of netrin mutant embryos. Double-mutant analyses indicate that Netrin and Schizo act independently. The schizo mutant phenotype can be suppressed by either expressing netrin in the CNS midline cells or by a reduction of the slit gene dose, indicating that the balance of attractive and repulsive signaling is impaired in schizo mutants. Overexpression of the schizo RNA in the CNS midline using the GAL4/UAS system leads to a slit phenocopy, suggesting that schizo primarily antagonizes Slit signaling. This is further supported by cell type-specific rescue experiments. The schizo gene generates at least two proteins containing a conserved Sec7 and a pleckstrin homology domain (PH) characteristic for guanine nucleotide exchange factors(GEF) acting on ARF GTPases, which are known to regulate endocytosis.In support of the notion that schizo regulates Slit expression via endocytosis, we found that block of endocytosis leads to a schizo-like phenotype. We thus propose that the balance of the two signaling cues Netrin and Slit can be regulated, controlling membrane dynamics.

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Section: Introductionmentioning

confidence: 79%

TheDrosophilaARF6-GEF Schizo controls commissure formation by regulating Slit

2004

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“…Furthermore, UNC-40 and UNC-5 are each capable of acting cell autonomously to orient growth cones either towards or away, respectively, from sources of UNC-6 (see Culotti and Kolodkin, 1996;Hedgecock and Norris, 1997;Merz and Culotti, 2000 and references therein). Importantly, ectopic expression of UNC-5 in neurons that normally only express UNC-40 and are attracted to UNC-6, resulted in a reorientation of axon growth that reflects a repulsive response to UNC-6 (Hamelin et al, 1993). This observation formed the basis of a new genetic screen that has recently led to the isolation of eight genes whose products are required for UNC-5-directed axon outgrowth .…”

Section: Elegans Body Wallmentioning

confidence: 97%

“…Genetic analyses have now established that interactions between the products of three genes, unc-5, unc-6, and unc-40, regulate the circumferential guidance of growth cones/axons (and the migration of cells) along the C. elegans body wall (for reviews see Culotti and Kolodkin, 1996;Hedgecock and Norris, 1997;Culotti and Merz, 1998;Branda and Stern, 1999;Merz and Culotti, 2000). More specifically, the vertebrate Netrin ortholog, UNC-6, is required for both dorsal and ventral guidance events (Hedgecock et al, 1990;Ishii et al, 1992;Wadsworth et al, 1996), the vertebrate DCC ortholog, UNC-40, is required for ventral (and to a lesser extent dorsal) guidance events (Hedgecock et al, 1990;Chan et al, 1996), and a novel Ig-superfamily member, UNC-5, is required exclusively for dorsally-directed axon guidance (LeungHagesteijn et al, 1992;Hamelin et al, 1993). Furthermore, UNC-40 and UNC-5 are each capable of acting cell autonomously to orient growth cones either towards or away, respectively, from sources of UNC-6 (see Culotti and Kolodkin, 1996;Hedgecock and Norris, 1997;Merz and Culotti, 2000 and references therein).…”

Section: Elegans Body Wallmentioning

confidence: 99%

Axon guidance at the midline choice point

Kaprielian

Runko

Imondi

2001

Developmental Dynamics

145

108

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The central nervous system (CNS) of higher organisms is bilaterally-symmetric. The transfer of information between the two sides of the nervous system occurs through commissures formed by neurons that project axons across the midline to the contralateral side of the CNS. Interestingly, these axons cross the midline only once. Other neurons extend axons that never cross the midline; they project exclusively on their own (ipsilateral) side of the CNS. Thus, the midline is an important choice point for several classes of pathfinding axons. Recent studies demonstrate that specialized midline cells play critical roles in regulating the guidance of both crossing and non-crossing axons at the ventral midline of the developing vertebrate spinal cord and the Drosophila ventral nerve cord. For example, these cells secrete attractive cues that guide commissural axons over long distances to the midline of the CNS. Furthermore, shortrange interactions between guidance cues present on the surfaces of midline cells, and their receptors expressed on the surfaces of pathfinding axons, allow commissural axons to cross the midline only once and prevent ipsilaterally-projecting axons from entering the midline. Remarkably, the molecular composition of commissural axon surfaces is dynamically-altered as they cross the midline. Consequently, commissural axons become responsive to repulsive midline guidance cues that they had previously ignored on the ipsilateral side of the midline. Concomitantly, commissural axons lose responsiveness to attractive guidance cues that had initially attracted them to the midline. Thus, these exquisitely regulated guidance systems prevent commissural axons from lingering within the confines of the midline and allow them to pioneer an appropriate pathway on the contralateral side of the CNS. Many aspects of midline guidance are controlled by mechanistically and evolutionarily-conserved ligand-receptor systems. Strikingly, recent studies demonstrate that these receptors are modular; the ectodomains determine ligand recognition and the cytoplasmic domains specify the response of an axon to a given guidance cue. Despite rapid and dramatic progress in elucidating the molecular mechanisms that control midline guidance, many questions remain.

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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 .…”

mentioning

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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Expression of the UNC-5 guidance receptor in the touch neurons of C. elegans steers their axons dorsally

Cited by 225 publications

References 16 publications

TheDrosophilaARF6-GEF Schizo controls commissure formation by regulating Slit

TheDrosophilaARF6-GEF Schizo controls commissure formation by regulating Slit

Axon guidance at the midline choice point

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

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