The SLIT family (SLIT1-3) of highly conserved glycoproteins was originally identified as ligands for the Roundabout (ROBO) family of single-pass transmembrane receptors, serving to provide repulsive axon guidance cues in the nervous system. Intriguingly, studies involving SLIT3 mutant mice suggest that SLIT3 might have crucial biological functions outside the neural context. Although these mutant mice display no noticeable neurological abnormalities, they present pronounced connective tissue defects, including congenital central diaphragmatic hernia, membranous ventricular septal defect, and osteopenia. We recently hypothesized that the phenotype observed in SLIT3-deficient mice may be tied to abnormalities in fibrillar collagen-rich connective tissue. Further research by our group indicates that both SLIT3 and its primary receptor, ROBO1, are expressed in fibrillar collagen-producing cells across various nonneural tissues. Global and constitutive SLIT3 deficiency not only reduces the synthesis and content of fibrillar collagen in various organs but also alleviates pressure overload-induced fibrosis in both the left and right ventricles. This review delves into the known phenotypes of SLIT3 mutants and the debated role of SLIT3 in vasculature and bone. Present evidence hints at SLIT3 acting as an autocrine regulator of fibrillar collagen synthesis, suggesting it as a potential antifibrotic treatment. However, the precise pathway and mechanisms through which SLIT3 regulates fibrillar collagen synthesis remain uncertain, presenting an intriguing avenue for future research.
Keywords: SLIT3; cardiac fibrosis; collagen; connective tissue; fibroblast.