Slit3, a member of the SLIT family of highly conserved glycoproteins, was initially recognized as a ligand for the Roundabout (ROBO) family of single-pass transmembrane receptors, crucial for repulsive axon guidance in the nervous system. However, it has since been found to have diverse functions beyond the neural context. It is involved in various biological processes such as fibrillar collagen synthesis regulation, which is associated with connective tissue development [1].

Slit3-deficient mice display no neurological abnormalities but have connective tissue defects like congenital central diaphragmatic hernia, membranous ventricular septal defect, and osteopenia, indicating its importance in non-neural tissues [1]. In adipose tissue, Slit3 secreted from M2-like macrophages promotes cold adaptation by stimulating sympathetic innervation and thermogenesis in mice [2]. In the heart, the SLIT3-ROBO1-signaling axis, with SLIT3 secreted by cardiac stromal cells, regulates postnatal cardiomyocyte hypertrophy induced by pressure overload [3]. Osteoblasts, not osteoclasts, are the major source of skeletal SLIT3, and targeting the SHN3/SLIT3 pathway can increase bone formation and enhance fracture healing [4,5,6]. Also, SLIT3 promotes myogenic differentiation, playing a sarcoprotective role [7], and it can regulate cardiac fibrosis and fibroblast differentiation via the RhoA/ROCK1 signaling pathway [8]. In the cornea, ER stress-induced upregulation of the SLIT3-ROBO4 pathway inhibits corneal epithelial injury repair and nerve regeneration [9].

In summary, Slit3 is a multifunctional protein. Its study through gene knockout (KO) and conditional knockout (CKO) mouse models has revealed its significant roles in connective tissue development, adipose tissue thermogenesis, cardiac hypertrophy, bone formation, muscle differentiation, cardiac fibrosis, and corneal repair. These findings suggest its potential as a therapeutic target in related disease areas such as fibrosis, metabolic disorders, cardiovascular diseases, bone loss, muscle loss, and corneal injury.