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, playing a role in providing repulsive axon guidance cues in the nervous system. However, it has crucial functions beyond the neural context, being involved in processes like connective tissue development and fibrosis regulation [1].

Studies on Slit3-deficient mice have shown significant phenotypes. These mice lack noticeable neurological abnormalities but present connective tissue defects such as congenital central diaphragmatic hernia, membranous ventricular septal defect, and osteopenia. Global and constitutive Slit3 deficiency reduces fibrillar collagen synthesis and content in various organs and alleviates pressure overload-induced fibrosis in both ventricles, indicating its role in fibrosis [1]. In adipose tissue, Slit3-deficient myeloid cells lead to cold-intolerance and increased weight, as Slit3 secreted by M2-like macrophages promotes cold adaptation by stimulating sympathetic innervation and thermogenesis [2]. In the heart, fibroblast and vascular mural cell-specific knockout of Slit3 decreases left ventricular hypertrophy and cardiac fibrosis after transverse aortic constriction, revealing its role in cardiac hypertrophy [3]. Also, conditional deletion of Slit3 in osteoclast-related cells shows no effect on bone parameters, suggesting osteoblasts as the major source of skeletal Slit3 [4].

In conclusion, Slit3 has diverse biological functions. Through gene knockout mouse models, its roles in connective tissue development, adipose tissue thermogenesis, cardiac hypertrophy, and bone-related processes have been revealed. These findings contribute to understanding diseases related to fibrosis, adipose tissue dysfunction, cardiac diseases, and bone disorders, providing potential therapeutic targets for these conditions.

References:

1. Gong, Lianghui, Si, Ming-Sing. 2023. SLIT3-mediated fibroblast signaling: a promising target for antifibrotic therapies. In American journal of physiology. Heart and circulatory physiology, 325, H1400-H1411. doi:10.1152/ajpheart.00216.2023. https://pubmed.ncbi.nlm.nih.gov/37830982/

2. Wang, Yi-Na, Tang, Yan, He, Zhihui, Qian, Shuwen, Tang, Qi-Qun. 2021. Slit3 secreted from M2-like macrophages increases sympathetic activity and thermogenesis in adipose tissue. In Nature metabolism, 3, 1536-1551. doi:10.1038/s42255-021-00482-9. https://pubmed.ncbi.nlm.nih.gov/34782792/

3. Liu, Xiaoxiao, Li, Baolei, Wang, Shuyun, Weiss, Stephen, Si, Ming-Sing. 2024. Stromal Cell-SLIT3/Cardiomyocyte-ROBO1 Axis Regulates Pressure Overload-Induced Cardiac Hypertrophy. In Circulation research, 134, 913-930. doi:10.1161/CIRCRESAHA.122.321292. https://pubmed.ncbi.nlm.nih.gov/38414132/

4. Li, Na, Inoue, Kazuki, Sun, Jun, Xu, Ren, Greenblatt, Matthew B. 2020. Osteoclasts are not a source of SLIT3. In Bone research, 8, 11. doi:10.1038/s41413-020-0086-3. https://pubmed.ncbi.nlm.nih.gov/32133214/