Repellent Signaling by Slit Requires the Leucine-Rich Repeats

Battye, Robin; Stevens, Adrienne; Perry, Robert L.; Jacobs, J. Roger

doi:10.1523/jneurosci.21-12-04290.2001

Cited by 69 publications

(62 citation statements)

References 44 publications

(31 reference statements)

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“…The source of this Sli must be the midline since within the nerve cord, the sli gene is not zygotically transcribed outside of the midline ( Figure 1a). In sli 2 mutant allele, which is genetically a null allele (Battye et al 2001), the mutant protein is not recognized by the monoclonal antibody raised against the C-terminal portion of the protein; in these embryos, the Sli staining of the commissural and longitudinal tracts was absent ( Figure 1c). These results indicate that the source of Sli in the connectives and commissures is unlikely the background.…”

Section: Resultsmentioning

confidence: 99%

“…Mapping the sli mutation in the sli 2 mutant: The molecular basis of sli 2 allele was previously reported as A / T transversion at the position 3321 bp (mRNA-A variant), which results in premature termination of Slit translation (K / Stop) at position 1024 aa (Battye et al 2001). To confirm this mutation in sli 2 chromosome, we amplified and sequenced the 450 bp of exon 16 covering the mutation site using forward primer: 59-CGATGCTTGCTACGGAAATC-39 (3092-3111 bp of mRNA-A) and reverse primer 59-CGTATAGTCGTCTGGACAG-39 (3518-3536 bp of mRNA-A).…”

Section: Ga957mentioning

confidence: 99%

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Regulation of Axon Guidance by Slit and Netrin Signaling in the Drosophila Ventral Nerve Cord

2007

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Netrin and Slit signaling systems play opposing roles during the positioning of longitudinal tracts along the midline in the ventral nerve cord of Drosophila embryo. It has been hypothesized that a gradient of Slit from the midline interacts with three different Robo receptors to specify the axon tract positioning. However, no such gradient has been detected. Moreover, overexpression of Slit at the midline has no effect on the positioning of these lateral tracts. In this article, we show that Slit is present outside of the midline along the longitudinal and commissural tracts. Sli from the midline, in a Robo-independent manner, is initially taken up by the commissural axon tracts when they cross the midline and is transported along the commissural tracts into the longitudinal connectives. These results are not consistent with a Sli gradient model. We also find that sli mRNA is maternally deposited and embryos that are genetically null for sli can have weaker guidance defects. Moreover, in robo or robo3 mutants, embryos with normal axon tracts are found and such robo embryos reach pupal stages and die, while robo3 mutant embryos develop into normal individuals and produce eggs. Interestingly, embryos from robo3 homozygous individuals fail to develop but have axon tracts ranging from normal to various defects: robo3 phenotype, robo phenotype, and slit-like phenotype, suggesting a more complex functional role for these genes than what has been proposed. Finally, our previous results indicated that netrin phenotype is epistatic to sli or robo phenotypes. However, it seems likely that this previously reported epistatic relationship might be due to the partial penetrance of the sli, robo, robo3 (or robo2) phenotypes. Our results argue that double mutant epistasis is most definitive only if the penetrance of the phenotypes of the mutants involved is complete.

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Section: Resultsmentioning

confidence: 99%

Section: Ga957mentioning

confidence: 99%

Regulation of Axon Guidance by Slit and Netrin Signaling in the Drosophila Ventral Nerve Cord

2007

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“…Similar to the proteins in this large family of molecules are the Slits and Robos, which contain LRR domains or both FNIII and Ig repeats in their ectodomains, respectively. Slits are large secreted proteins involved in axonal guidance, which requires their LRR region for repellent signaling (17,(42)(43)(44)(45). Interestingly, the Slits and Robos have been shown to interact through the LRR region of the Slits and the Ig domains of Robo (44 -47).…”

Section: Discussionmentioning

confidence: 99%

The SALM Family of Adhesion-like Molecules Forms Heteromeric and Homomeric Complexes

Seabold

Wang

Chang

et al. 2008

Journal of Biological Chemistry

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Synaptic adhesion-like molecules (SALMs) are a newly discovered family of adhesion molecules that play roles in synapse formation and neurite outgrowth. The SALM family is comprised of five homologous molecules that are expressed largely in the central nervous system. SALMs 1-3 contain PDZ-binding domains, whereas SALMs 4 and 5 do not. We are interested in characterizing the interactions of the SALMs both among the individual members and with other binding partners. In the present study, we focused on the interactions formed by the five SALM members in rat brain and heterologous cells. In brain, we found that SALMs 1-3 strongly co-immunoprecipitated with each other, whereas SALMs 4 and 5 did not, suggesting that SALMs 4 and 5 mainly form homomeric complexes. In heterologous cells transfected with SALMs, co-immunoprecipitation studies showed that all five SALMs form heteromeric and homomeric complexes. We also determined if SALMs could form trans-cellular associations between transfected heterologous cells. Both SALMs 4 and 5 formed homophilic, but not heterophilic associations, whereas no trans associations were formed by the other SALMs. The ability of SALM4 to form trans interactions is due to its extracellular N terminus because chimeras of SALM4 N terminus and SALM2 C terminus can form trans interactions, whereas chimeras of SALM2 N terminus and SALM4 C terminus cannot. Co-culture experiments using HeLa cells and rat hippocampal neurons expressing the SALMs showed that SALM4 is recruited to points of contact between the cells. In neurons, these points of contact were seen in both axons and dendrites.Critical steps in the development of the nervous system, including cell migration, neurite outgrowth, growth cone guidance, and synapse formation, depend on cellular interactions mediated by adhesion molecules (1-4). A number of adhesion molecules that are essential to the proper development of the nervous system have been identified (5-7). The importance of these molecules is illustrated in cases of dysfunctional adhesion molecules that have been associated with specific disorders in humans, including SLITRK1 in Tourette syndrome (8) and neuroligin in autism (9, 10). Whereas our understanding of the role of adhesion molecules in neuronal development is rapidly increasing, little is known about their functions, and it is likely that many remain to be identified.Synaptic adhesion-like molecules (SALMs) 2 are a recently identified class of adhesion molecules that are highly enriched in brain (11-13). All five members of the SALM family contain extracellular leucine-rich repeats (LRR), an immunoglobulin C2-like (IgC2) domain, a fibronectin type III (FNIII) domain, a transmembrane domain, and a cytoplasmic C-terminal tail. SALMs 1-3 contain a C-terminal PDZ-binding domain (PDZ-BD), which associates with the PSD-95 family of proteins (11-13). SALMs are expressed early in the developing nervous system and persist into adulthood. They are present at the synaptic membrane as well as at non-synaptic locations. SALM1 overe...

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“…Structure-function analysis in vertebrate and Drosophila revealed that the LRRs of slits are required and sufficient to mediate its repulsive activities in neurons. [108][109][110][111] More recent studies have shown that in Drosophila all three Robo receptors compete for a single active binding site in the second LRR of Slit. 108 Neither the FN3 domains nor Robo dimerization are required for slit binding.…”

Section: The Slits and Robosmentioning

confidence: 99%

The brain within the tumor: new roles for axon guidance molecules in cancers

2005

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Slits, semaphorins and netrins are three families of proteins that can attract or repel growing axons and migrating neurons in the developing nervous system of vertebrates and invertebrates. Recent studies have shown that they are widely expressed outside the nervous system and that they may play important roles in cancers. Several of the genes encoding these proteins are localized on chromosomal region associated with frequent loss-of-heterozygosity in tumors and cancer cell lines and there is also significant hypermethylation of their promoter suggesting that they may act as tumor suppressors. In addition, proteins in all these families and their receptors appear to control the vascularization of the tumors. Last, many axon guidance molecules also regulate cell migration and apoptosis in normal and tumorigenic tissues. Overall, this suggests that molecules that could mimick or block the activity of axon guidance molecules may be used as therapeutic agents for the treatment of malignancy.

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Repellent Signaling by Slit Requires the Leucine-Rich Repeats

Cited by 69 publications

References 44 publications

Regulation of Axon Guidance by Slit and Netrin Signaling in the Drosophila Ventral Nerve Cord

Regulation of Axon Guidance by Slit and Netrin Signaling in the Drosophila Ventral Nerve Cord

The SALM Family of Adhesion-like Molecules Forms Heteromeric and Homomeric Complexes

The brain within the tumor: new roles for axon guidance molecules in cancers

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