Disease relevance of Slit2

• To investigate the effect of the N-terminal Slit2 protein on neuronal survival and development, recombinant human N-terminal Slit2 (N-Slit2) was assayed against isolated embryonic chick dorsal root ganglion sensory, ciliary ganglion and paravertebral sympathetic neurons [1].

High impact information on Slit2

• 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].
• Slit1 and Slit2 cooperate to prevent premature midline crossing of retinal axons in the mouse visual system [3].
• Chemorepulsion of neuronal migration by Slit2 in the developing mammalian forebrain [4].
• Thus, Slit2, which is expressed by the choroid plexus and the septum, acts as a chemorepulsive factor for neuronal migration [4].
• Loss-of-function mutations in Slit2 and Robo1 yield similar phenotypes, characterized by disorganized end buds (EBs) reminiscent of those present in Ntn1(-/-) glands, suggesting that SLIT2 and NTN1 function in concert during mammary development [5].

Biological context of Slit2

• Slit2 and netrin 1 act synergistically as adhesive cues to generate tubular bi-layers during ductal morphogenesis [5].

Anatomical context of Slit2

• Slit2 has been shown to bind Robo1, mediating both neuronal and axonal guidance in the developing central nervous system (CNS), (Brose et al., 1999; Hu, H., 1999. Chemorepulsion of neuronal migration by Slit2 in the developing mammalian forebrain. Neuron 23, 703-711) [6].
• Slit2 and Slit1/2 double mutants display malformations in callosal development, and in corticothalamic and thalamocortical targeting, as well as optic tract defects [7].
• During the bell stage, Robo1 and Slit2 expression became restricted to the dental epithelia, while Slit3 continued in the dental mesenchyme [8].
• Furthermore, analysis of the expression of candidate molecules in the basal telencephalon and hypothalamus of Nkx2-1 mutants suggests that Slit2 contributes to this activity [9].
• N-Slit2 promoted significant levels of neuronal survival and neurite extension in all of these populations [1].

Regulatory relationships of Slit2

• Slit2 was expressed at the tips of the UT and both Slit2 and Slit3 were expressed at the far proximal end of the comma shaped and S-shaped bodies [6].
• In the developing corpus callosum, Slit2 expressed by the glial wedge guides callosal axons before they cross the midline, as they approach the corticoseptal boundary [10].

Other interactions of Slit2

• Slit1 and Slit2, two known chemorepellents for developing axons, can mimic this effect [11].
• In contrast, expression of Slit2 and -3 as well Robo1, and -2 was largely restricted to mesenchymal tissue components of the tooth until the bell stage [8].
• We now demonstrate that Slit-2 and Slit-3 are developmentally regulated in embryonic murine lung [12].
• However, although Probst's bundles formed consistently at the location of the glial wedge, both GAP-43 (-/-) and GAP-43 (+/+) cortical axons were still repulsed by Slit-2 in vitro, precluding failure of this deflective signal from the glial wedge as the source of the phenotype [13].

Analytical, diagnostic and therapeutic context of Slit2

• Immunohistochemistry demonstrates Slit-2 and Slit-3 expression by the pulmonary mesenchyme and airway epithelium [12].

References