Alternative titles; symbols
HGNC Approved Gene Symbol: SLIT2
Cytogenetic location: 4p15.31 Genomic coordinates (GRCh38) : 4:20,251,905-20,620,561 (from NCBI)
In Drosophila embryogenesis, the 'slit' gene has been shown to play a critical role in central nervous system midline formation. Itoh et al. (1998) cloned the SLIT2 gene, a human homolog of the Drosophila 'slit' gene. They also cloned 2 additional human 'slit' homologs, which they termed SLIT1 (603742) and SLIT3 (603745), as well as the rat homolog, Slit1. Each SLIT gene encodes a putative secreted protein, which contains conserved protein-protein interaction domains including leucine-rich repeats and epidermal growth factor-like (see 131530) motifs, similar to those of the Drosophila protein. The SLIT2 cDNA encodes a 1,529-amino acid polypeptide with 44.3% similarity to the Drosophila 'slit' protein. Northern blot analysis revealed that the human SLIT2 gene was expressed as an approximately 8.5-kb transcript primarily in the spinal cord. SLIT1 and SLIT3 mRNAs were primarily expressed in the brain and thyroid, respectively. In situ hybridization studies indicated that the rat Slit1 mRNA was specifically expressed in the neurons of fetal and adult forebrains. These data suggested that the SLIT genes form an evolutionarily conserved group in vertebrates and invertebrates, and that the mammalian SLIT proteins may participate in the formation and maintenance of the nervous and endocrine systems by protein-protein interactions.
Schembri et al. (2009) noted that the microRNA-218-1 (MIR218-1; 616770) gene is located within an intron of the SLIT2 gene. Small et al. (2010) reported that the mouse Mir218-1 gene is located in intron 14 of the Slit2 gene.
By fluorescence in situ hybridization, Georgas et al. (1999) mapped the human SLIT2 gene to chromosome 4p15.2.
Small et al. (2010) stated that the mouse Slit2 gene maps to chromosome 5.
Brose et al. (1999) showed that, like their Drosophila counterpart, the vertebrate SLIT genes are expressed by cells at the ventral midline of the nervous system. They further demonstrated that SLIT proteins are ligands for ROBO proteins (see ROBO1; 602430) in both Drosophila and vertebrates, and that in vertebrates SLIT2 can repel spinal motor axons in culture. Together with genetic data (Kidd et al., 1999), these results established that SLIT is a repulsive ligand for ROBO in Drosophila and that SLIT proteins have a conserved function in repulsive axon guidance. Li et al. (1999) obtained similar results for vertebrate SLIT proteins.
Wu et al. (1999) reported that the secreted protein Slit repels neuronal precursors migrating from the anterior subventricular zone in the telencephalon to the olfactory bulb. Wu et al. (1999) provided direct demonstration of a molecular cue whose concentration gradient guides the direction of migrating neurons. Both the Slit1 and Slit2 genes are expressed in murine postnatal septum and the neocortex. Wu et al. (1999) concluded that their data support a common guidance mechanism for axon projection and neuronal migration, and suggested that Slit may provide a molecular tool with potential therapeutic applications in controlling and directing cell migration.
Axonal growth cones that cross the nervous system midline change their responsiveness to midline guidance cues: they become repelled by the repellent Slit and simultaneously lose responsiveness to the attractant netrin (601614). These mutually reinforcing changes help to expel growth cones from the midline by making a once-attractive environment appear repulsive. Stein and Tessier-Lavigne (2001) provided evidence that these 2 changes are causally linked: in the growth cones of embryonic Xenopus spinal axons, activation of the Slit receptor Robo silences the attractive effect of netrin-1, but not its growth-stimulatory effect, through direct binding of the cytoplasmic domain of Robo to that of the netrin receptor DCC (120470). Biologically, this hierarchical silencing mechanism helps to prevent a tug-of-war between attractive and repulsive signals in the growth cone that might cause confusion. Molecularly, silencing is enabled by a modular and interlocking design of the cytoplasmic domains of these potentially antagonistic receptors that predetermines the outcome of their simultaneous activation. Note that an expression of concern was published for the article by Stein and Tessier-Lavigne (2001).
Wu et al. (2001) reported that SLIT2, a secreted protein known for its role of repulsion in axon guidance and neuronal migration, can also inhibit leukocyte chemotaxis induced by chemotactic factors. Slit inhibition of the chemokine-induced chemotaxis can be reconstituted by the coexpression of a chemokine receptor containing 7 transmembrane domains (CXCR4; 162643) and Roundabout (ROBO1; 602430), a Slit receptor containing a single transmembrane domain. Thus, Wu et al. (2001) concluded that there is a functional interaction between single- and 7-transmembrane receptors, and that the results revealed the activity of a neuronal guidance cue in regulating leukocyte migration. They suggested that these results indicate that there may be a general conservation of guidance mechanisms underlying metazoan cell migration.
By confocal microscopy of rat cerebellar tissues, Guan et al. (2007) showed that the leading growth cone was responsible for sensing extracellular Slit2, and that a propagating Ca(2+) wave from the leading growth cone to the soma was responsible for inducing reversal in direction of soma translocation in response to a frontal gradient of Slit2. Reversal of migration induced by Slit2 required Rhoa (165390) activity and correlated with an anterior-to-posterior redistribution of active Rhoa in the soma. Guan et al. (2007) concluded that long-range Ca(2+) signaling coordinates SLIT2-induced changes in motility at 2 distant parts of migrating neurons by regulating RHOA distribution.
Zhou et al. (2013) tested whether the induction of adult stem cells could repair chemoradiation-induced tissue injury and prolong overall survival in mice. Zhou et al. (2013) found that intestinal stem cells expressed Slit2 and its single-span transmembrane cell-surface receptor Robo1. Partial genetic deletion of Robo1 decreased intestinal stem cell numbers and caused villus hypotrophy, whereas a Slit2 transgene increased intestinal stem cell numbers and triggered villus hypertrophy. During lethal dosages of chemoradiation, administering a short pulse of R-spondin-1 (Rspo1; 609595), a Wnt agonist, plus Slit2 reduced intestinal stem cell loss, mitigated gut impairment, and protected animals from death, without concomitantly decreasing tumor sensitivity to chemotherapy. Therefore, Zhou et al. (2013) concluded that Rspo1 and Slit2 may act as therapeutic adjuvants to enhance host tolerance to aggressive chemoradiotherapy for eradicating metastatic cancers.
Tavora et al. (2020) used mouse models of breast and lung cancer to investigate whether endothelial cells also have active instructive roles in the dissemination of cancer. They purified genetically tagged endothelial ribosomes and their associated transcripts from highly and poorly metastatic tumors. Deep sequencing revealed that metastatic tumors induced expression of the axon-guidance gene Slit2 in endothelium, establishing differential expression between the endothelial (high Slit2 expression) and tumoral (low Slit2 expression) compartments. Endothelial-derived Slit2 protein and its receptor Robo1 promoted the migration of cancer cells towards endothelial cells and intravasation. Deleting endothelial Slit2 suppressed metastatic dissemination in mouse models of breast and lung cancer. Conversely, deletion of tumoral Slit2 enhanced metastatic progression. Tavora et al. (2020) identified double-stranded RNA derived from tumor cells as an upstream signal that induced expression of endothelial Slit2 by acting on the RNA-sensing receptor Tlr3 (603029). Accordingly, a set of endogenous retroviral element RNAs were upregulated in metastatic cells and detected extracellularly. Thus, cancer cells co-opt innate RNA sensing to induce a chemotactic signaling pathway in endothelium that drives intravasation and metastasis. Tavora et al. (2020) concluded that endothelial cells have a direct instructive role in driving metastatic dissemination, and that a single gene (Slit2) can promote or suppress cancer progression depending on its cellular source.
By whole-exome sequencing in 26 families with genetically unsolved congenital anomalies of kidney and urinary tract (CAKUT), Hwang et al. (2015) identified 3 unrelated individuals with heterozygous missense mutations in the SLIT2 gene. For 2 affected males, one with bilateral subcortical cysts and the other with right renal agenesis, no parental DNA was available. A Macedonian male (family A4736) with right multicystic dysplastic kidney had an S566N substitution (c.1697G-A, NM_004787.1) inherited from his unaffected carrier mother. Hamosh (2017) noted that this variant was present in 23 of 272,310 alleles in the gnomAD database and was also present in the ExAC database (September 12, 2017).
To investigate the role of Slit proteins in retinal ganglion cell axon guidance, Plump et al. (2002) used gene targeting to generate mice deficient in either Slit1 or Slit2. The knockout mice exhibited few retinal ganglion cell axon guidance defects and the authors concluded that Slit1 and Slit2 deficiency alone does not cause significant defects in axon guidance within the developing visual system. In contrast, they demonstrated that Slit1/2 double mutants develop severe and persistent axon guidance defects in the visual system. Using lipophilic dye tracing and immunohistochemistry, they detected defects in the double knockout mice, including the formation of a second, ectopic optic chiasm; aberrant growth of retinal axons into the contralateral optic nerve; and axon wandering defects in the ventral diencephalon. Plump et al. (2002) concluded that Slit1 and Slit2 play a critical role in channeling retinal axons toward their appropriate midline crossing point, serving as inhibitors for growth into inappropriate regions of the brain. The authors hypothesized that the complementary domains of Slit1 and Slit2 expression surrounding the path of the ingrowing retinal axons establish a corridor through which retinal axons can travel, resulting in the correct positioning of the optic chiasm within the brain.
Using immunohistochemistry and axon tracing experiments, Bagri et al. (2002) presented a detailed characterization of abnormal axonal projections within the forebrain of Slit2 knockout and Slit1/2 double knockout mice (Plump et al. (2002)). They provided in vivo evidence that Slit proteins are regulators of guidance of corticofugal, callosal, thalamocortical, serotonergic, and dopaminergic projections in the embryonic forebrain. The authors concluded that Slit proteins in the brain appear to contribute to the maintenance of dorsal position by prevention of axonal growth into ventral regions, the prevention of axonal extension toward and across the midline, and the channeling of axons toward particular regions.
Grieshammer et al. (2004) found that mice lacking either Slit2 or its receptor, Robo2 (602431), developed supernumerary uretic buds that remained inappropriately connected to the nephric duct. In addition, Gdnf (600837) expression was inappropriately maintained in anterior nephrogenic mesenchyme in these mutants. Grieshammer et al. (2004) concluded that SLIT2/ROBO2 signaling restricts the extent of the GDNF expression domain, thereby precisely positioning the site of kidney induction.
Bagri, A., Marin, O., Plump, A. S., Mak, J., Pleasure, S. J., Rubenstein, J. L. R., Tessier-Lavigne, M. Slit proteins prevent midline crossing and determine the dorsoventral position of major axonal pathways in the mammalian forebrain. Neuron 33: 233-248, 2002. [PubMed: 11804571] [Full Text: https://doi.org/10.1016/s0896-6273(02)00561-5]
Brose, K., Bland, K. S., Wang, K. H., Arnott, D., Henzel, W., Goodman, C. S., Tessier-Lavigne, M., Kidd, T. Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance. Cell 96: 795-806, 1999. [PubMed: 10102268] [Full Text: https://doi.org/10.1016/s0092-8674(00)80590-5]
Georgas, K., Burridge, L., Smith, K., Holmes, G. P., Chenevix-Trench, G., Ioannou, P. A., Little, M. H. Assignment of the human slit homologue SLIT2 to human chromosome band 4p15.2. Cytogenet. Cell Genet. 86: 246-247, 1999. [PubMed: 10575218] [Full Text: https://doi.org/10.1159/000015351]
Grieshammer, U., Ma, L., Plump, A. S., Wang, F., Tessier-Lavigne, M., Martin, G. R. SLIT2-mediated ROBO2 signaling restricts kidney induction to a single site. Dev. Cell 6: 709-717, 2004. [PubMed: 15130495] [Full Text: https://doi.org/10.1016/s1534-5807(04)00108-x]
Guan, C., Xu, H., Jin, M., Yuan, X., Poo, M. Long-range Ca(2+) signaling from growth cone to soma mediates reversal of neuronal migration induced by Slit-2. Cell 129: 385-395, 2007. [PubMed: 17448996] [Full Text: https://doi.org/10.1016/j.cell.2007.01.051]
Hamosh, A. Personal Communication. Baltimore, Md. September 12, 2017.
Hwang, D.-Y., Kohl, S., Fan, X., Vivante, A., Chan, S., Dworschak, G. C., Schulz, J., van Eerde, A. M., Hilger, A. C., Gee, H. Y., Pennimpede, T., Herrmann, B. G. Mutations of the SLIT2-ROBO2 pathway genes SLIT2 and SRGAP1 confer risk for congenital anomalies of the kidney and urinary tract. Hum. Genet. 134: 905-916, 2015. [PubMed: 26026792] [Full Text: https://doi.org/10.1007/s00439-015-1570-5]
Itoh, A., Miyabayashi, T., Ohno, M., Sakano, S. Cloning and expressions of three mammalian homologues of Drosophila slit suggest possible roles for Slit in the formation and maintenance of the nervous system. Molec. Brain Res. 62: 175-186, 1998. [PubMed: 9813312] [Full Text: https://doi.org/10.1016/s0169-328x(98)00224-1]
Kidd, T., Bland, K. S., Goodman, C. S. Slit is the midline repellent for the Robo receptor in Drosophila. Cell 96: 785-794, 1999. [PubMed: 10102267] [Full Text: https://doi.org/10.1016/s0092-8674(00)80589-9]
Li, H., Chen, J., Wu, W., Fagaly, T., Zhou, L., Yuan, W., Dupuis, S., Jiang, Z., Nash, W., Gick, C., Ornitz, D. M., Wu, J. Y., Rao, Y. Vertebrate Slit, a secreted ligand for the transmembrane protein Roundabout, is a repellent for olfactory bulb axons. Cell 96: 807-818, 1999. [PubMed: 10102269] [Full Text: https://doi.org/10.1016/s0092-8674(00)80591-7]
Plump, A. S., Erskine, L., Sabatier, C., Brose, K., Epstein, C. J., Goodman, C. S., Mason, C. A., Tessier-Lavigne, M. Slit1 and Slit2 cooperate to prevent premature midline crossing of retinal axons in the mouse visual system. Neuron 33: 219-232, 2002. [PubMed: 11804570] [Full Text: https://doi.org/10.1016/s0896-6273(01)00586-4]
Schembri, F., Sridhar, S., Perdomo, C., Gustafson, A. M., Zhang, X., Ergun, A., Lu, J., Liu, G., Zhang, X., Bowers, J., Vaziri, C., Ott, K., Sensinger, K., Collins, J. J., Brody, J. S., Getts, R., Lenburg, M. E., Spira, A. MicroRNAs as modulators of smoking-induced gene expression changes in human airway epithelium. Proc. Nat. Acad. Sci. 106: 2319-2324, 2009. [PubMed: 19168627] [Full Text: https://doi.org/10.1073/pnas.0806383106]
Small, E. M., Sutherland, L. B., Rajagopalan, K. N., Wang, S., Olson, E. N. MicroRNA-218 regulates vascular patterning by modulation of Slit-Robo signaling. Circ. Res. 107: 1336-1344, 2010. [PubMed: 20947829] [Full Text: https://doi.org/10.1161/CIRCRESAHA.110.227926]
Stein, E., Tessier-Lavigne, M. Hierarchical organization of guidance receptors: silencing of netrin attraction by Slit through a Robo/DCC receptor complex. Science 291: 1928-1938, 2001. Note: Expression of Concern: Science 378: 1284 only, 2022. [PubMed: 11239147] [Full Text: https://doi.org/10.1126/science.1058445]
Tavora, B., Mederer, T., Wessel, K. J., Ruffing, S., Sadjadi, M., Missmahl, M., Ostendorf, B. N., Liu, X., Kim, J.-Y., Olsen, O., Welm, A. L., Goodarzi, H., Tavazoie, S. F. Tumoural activation of TLR3-SLIT2 axis in endothelium drives metastasis. Nature 586: 299-304, 2020. [PubMed: 32999457] [Full Text: https://doi.org/10.1038/s41586-020-2774-y]
Wu, J. Y., Feng, L., Park, H.-T., Havlioglu, N., Wen, L., Tang, H., Bacon, K. B., Jiang, Z., Zhang, X., Rao, Y. The neuronal repellent Slit inhibits leukocyte chemotaxis induced by chemotactic factors. Nature 410: 948-952, 2001. [PubMed: 11309622] [Full Text: https://doi.org/10.1038/35073616]
Wu, W., Wong, K., Chen, J., Jiang, Z., Dupuis, S., Wu, J. Y., Rao, Y. Directional guidance of neuronal migration in the olfactory system by the protein Slit. Nature 400: 331-336, 1999. [PubMed: 10432110] [Full Text: https://doi.org/10.1038/22477]
Zhou, W.-J., Geng, Z. H., Spence, J. R., Geng, J.-G. Induction of intestinal stem cells by R-spondin 1 and Slit2 augments chemoradioprotection. Nature 501: 107-111, 2013. [PubMed: 23903657] [Full Text: https://doi.org/10.1038/nature12416]