Disease relevance of Slit1

• In contrast to Sema3F, Slit-1 is dispensable for fasciculation of basal vomeronasal neuron axons but is critical for targeting these axons to the posterior AOB [1].

High impact information on Slit1

• Mice deficient in Slit2 and, even more so, mice deficient in both Slit1 and Slit2 show significant axon guidance errors in a variety of pathways, including corticofugal, callosal, and thalamocortical tracts [2].
• We report that Slit proteins, a family of secreted chemorepellents, are crucial for the proper development of several major forebrain tracts [2].
• In Drosophila, the Slit protein regulates midline axon crossing through repulsion [3].
• Our results indicate that Slit proteins repel retinal axons in vivo and cooperate to establish a corridor through which the axons are channeled, thereby helping define the site in the ventral diencephalon where the optic chiasm forms [3].
• In vitro assays show that Slit1-Slit3 chemorepel VNO axons, suggesting that basal axons are guided to the posterior AOB due to chemorepulsive activity of Slits in the anterior AOB [4].

Biological context of Slit1

• In search of novel molecules involved in tooth morphogenesis, we analyzed mRNA expression of Slit1, -2 and -3, earlier characterized as secreted signals needed for axonal pathfinding and their two receptors Robo1 and -2 (Roundabout1 and -2) in the developing mouse first molar [5].
• First described as an axonal guidance cue through its repulsive effect on neurons expressing its receptor Roundabout (Robo), the Slit ligand has effects on cell migration, axon branching and elongation [6].
• In situ hybridization analysis showed that after Fgf4 downregulation in the SEK, Slit1 expression persisted in the deep compartment of the knot [7].
• Roundabout receptors are molecular guidance molecules that function by interaction with Slit proteins to regulate axon guidance, neuronal migration, and leukocyte chemotaxis [8].
• Conserved modularity and potential for alternate splicing in mouse and human Slit genes [9].

Anatomical context of Slit1

• Slit2 and Slit1/2 double mutants display malformations in callosal development, and in corticothalamic and thalamocortical targeting, as well as optic tract defects [10].
• Slit1 was expressed in the metanephric mesenchyme (MM) surrounding the invading ureteric tree (UT) [11].
• In situ hybridization analysis showed that Slit1 mRNAs were expressed in the primary enamel knot of the bud and cap stage tooth germ and later the expression continued in the secondary enamel knots of the late cap and bell stage tooth [5].
• In adult mice lacking Slit1, small chains of SVZ-derived cells migrate caudally into the corpus callosum, supporting a role for Slits in orienting the migration of SVZ cells [12].
• To investigate Slit signalling in forebrain development, we generated Robo1 knockout mice by targeted deletion of exon 5 of the Robo1 gene [10].

Associations of Slit1 with chemical compounds

• In addition, glypican-1, a heparan sulfate proteoglycan that serves as a high-affinity receptor for Slit protein, was coexpressed with slit2 mRNA in the reactive astrocytes [13].
• The genomic structure of all Slit genes demonstrated considerable modularity in the placement of exon-intron boundaries such that individual leucine-rich repeat motifs were encoded by individual 72 bp exons [9].
• Projection neurons, identified by lack of GABA staining, did not respond to Slit, either by branching or elongation [14].

Regulatory relationships of Slit1

• Slit1 and slit2 proteins control the development of the lateral olfactory tract [15].
• Finally, we show that Robo4 is the only Robo family member expressed in primary endothelial cells and that application of Slit inhibits their migration [16].

Other interactions of Slit1

• These results demonstrate that whereas Slit1 and Slit2 are not necessary for tangential migration of interneurons to the cortex, these proteins regulate neuronal migration within the basal telencephalon by controlling cell positioning close to the midline [17].
• Therefore, our study showed that the septum chemorepellent is a combination of Slit1 and Slit2 and that these molecules play a significant role in olfactory bulb axon guidance in vivo [15].
• To determine whether members of the Netrin-1 and Slit families and their receptors are expressed after central nervous system (CNS) injury, we performed in situ hybridization for netrin-1, slit-1, 2 and 3, and their receptors (dcc, unc5h-1, 2 and 3, robo-1, 2 and 3) 8 days, 2-3 months and 12-18 months after traumatic lesions of rat cerebellum [18].

Analytical, diagnostic and therapeutic context of Slit1

• Using long distance PCR coupled with in silico mapping, we determined the genomic structure of all three Slit genes in mouse and man [9].
• We have investigated the utility of Slit Scan Flow Cytometry (SSFCM) for measuring the frequencies of malformed sperm heads in control and mutagen treated B6C3F1/CRL mice [19].

References