The Second Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, People's Republic of China.
Division of Cardiac Surgery, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, United States.
Am J Physiol Heart Circ Physiol. 2023 Dec 1;325(6):H1400-H1411. doi: 10.1152/ajpheart.00216.2023. Epub 2023 Oct 13.
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.
SLIT 家族（SLIT1-3）是高度保守的糖蛋白，最初被鉴定为 Roundabout（ROBO）家族单次跨膜受体的配体，为神经系统中的排斥性轴突导向提供线索。有趣的是，涉及 SLIT3 突变小鼠的研究表明，SLIT3 可能在神经背景之外具有至关重要的生物学功能。尽管这些突变小鼠没有表现出明显的神经异常，但它们表现出明显的结缔组织缺陷，包括先天性中央膈疝、膜性室间隔缺损和骨质疏松症。我们最近假设 SLIT3 缺陷小鼠观察到的表型可能与纤维状胶原丰富的结缔组织异常有关。我们小组的进一步研究表明，SLIT3 及其主要受体 ROBO1 在各种非神经组织的纤维状胶原产生细胞中表达。全身性和组成性 SLIT3 缺乏不仅降低了各种器官中纤维状胶原的合成和含量，而且还减轻了左右心室压力超负荷诱导的纤维化。这篇综述深入探讨了 SLIT3 突变体的已知表型以及 SLIT3 在血管和骨骼中的争议作用。目前的证据表明 SLIT3 作为纤维状胶原合成的自分泌调节剂发挥作用，提示其可能成为一种潜在的抗纤维化治疗方法。然而，SLIT3 调节纤维状胶原合成的确切途径和机制仍不确定，这为未来的研究提供了一个有趣的途径。
