Alternative titles; symbols
HGNC Approved Gene Symbol: SLIT1
Cytogenetic location: 10q24.1 Genomic coordinates (GRCh38) : 10:96,998,038-97,185,959 (from NCBI)
Members of the SLIT family, such as SLIT1, are secreted glycoproteins that bind and activate ROBO receptors (see ROBO1; 602430) and function in axon guidance during development (Xiao et al., 2011).
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 SLIT1, a human homolog of the Drosophila 'slit' gene. They also cloned 2 additional human 'slit' homologs, which they termed SLIT2 (603746) and SLIT3 (603745), as well as the rat homolog, Slit1. Each SLIT gene encodes a putative secreted protein that 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 SLIT1 cDNA encodes a 1,534-amino acid polypeptide with 43.5% similarity to the Drosophila 'slit' protein. Northern blot analysis revealed that the human SLIT1 gene was expressed as a major 8.4- and a minor 5.9-kb transcript primarily in the brain. SLIT2 and SLIT3 mRNAs were primarily expressed in the spinal cord 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.
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. They 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 the 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.
Using cocultured explants of mouse embryonic retina, Plump et al. (2002) found that Slit1, like Slit2, is a potent inhibitor of retinal axon growth, inducing a similar decrease in the extent of outgrowth to that seen in the presence of Slit2.
By PCR analysis of radiation hybrid panels, Nakayama et al. (1998) mapped the SLIT1 gene, which they referred to as the MEGF4 gene, to chromosome 10q23.3-q24.
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.
In the mouse ventral spinal cord, Hochstim et al. (2008) identified 3 subtypes of white matter astrocytes with differential gene expression corresponding to position. Astrocytes expressing both Reln (600514) and Slit1 were in the ventrolateral domain, those expressing Reln only were at the dorsolateral domain, and those expressing Slit1 only were at the ventromedial domain. The distinct positions of these astrocytes were specified by varying expression of the homeodomain transcription factors Pax6 (607108) and Nkx6.1 (602563). The findings indicated that positional identity is an organizing principle underlying phenotypic diversity among white matter astrocytes, as well as among neurons, and that this diversity is prespecified within precursor cells in the germinal zone of the CNS.
Using a zebrafish model, Xiao et al. (2011) showed that the type IV collagen Col4a5 (303630) on the surface of the tectum basement membrane bound Slit1 and guided retinal ganglion cell axons expressing Robo2.
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]
Hochstim, C., Deneen, B., Lukaszewicz, A., Zhou, Q., Anderson, D. J. Identification of positionally distinct astrocyte subtypes whose identities are specified by a homeodomain code. Cell 133: 510-522, 2008. [PubMed: 18455991] [Full Text: https://doi.org/10.1016/j.cell.2008.02.046]
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]
Nakayama, M., Nakajima, D., Nagase, T., Nomura, N., Seki, N., Ohara, O. Identification of high molecular weight proteins with multiple EGF-like motifs by motif-trap screening. Genomics 51: 27-34, 1998. [PubMed: 9693030] [Full Text: https://doi.org/10.1006/geno.1998.5341]
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]
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]
Xiao, T., Staub, W., Robles, E., Gosse, N. J., Cole, G. J., Baier, H. Assembly of lamina-specific neuronal connections by slit bound to type IV collagen. Cell 146: 164-176, 2011. [PubMed: 21729787] [Full Text: https://doi.org/10.1016/j.cell.2011.06.016]