Sema5a, short for Semaphorin 5A, is a crucial molecule involved in multiple biological processes. It functions as a bifunctional guidance cue in neuronal development, interacting with heparan sulfate (HS) and chondroitin sulfate (CS) glycosaminoglycans (GAGs) to exert attractive and inhibitory effects on neuronal growth respectively [3]. It is also associated with pathways like ECM receptor interaction [2]. Sema5a is important in the development of the nervous system and has implications in various diseases, highlighting its overall biological importance. Genetic models, such as mouse models, are valuable for studying its functions.

In pancreatic adenocarcinoma (PDAC), the Sema5a-PLXNB3 axis promotes liver metastasis outgrowth by enhancing the Warburg effect. Intrasplenic injection mouse models and Kras G12D/Trp53 R172H/Pdx1-Cre (KPC) mouse models were used to show that M2 type tumor-associated macrophages (TAMs)-derived Sema5a binds to its tumor cell-expressed receptor PLXNB3, promoting tumor cell proliferation and survival via enhancing aerobic glycolysis [1]. In rheumatoid arthritis (RA), Sema5a expression is increased. Sema5a-mAbs treatment in a collagen-induced arthritis (CIA) model (a type of mouse model) significantly attenuated joint injury and the inflammatory response. Transcriptome sequencing and angiogenesis-related experiments in Sema5a-transfected fibroblast-like synoviocytes (FLSs) from healthy controls, along with rescue experiments in Sema5a-/-CIA mice, verified that Sema5a promotes FLS proliferation and angiogenesis, and that the TSP1 domain of Sema5a is essential for pannus formation in RA [4].

In conclusion, Sema5a plays essential roles in biological processes such as neuronal growth regulation and in disease-related processes like cancer metastasis and arthritis development. Mouse models, including KO/CKO models as seen in the RA study, have been instrumental in revealing these functions. Understanding Sema5a functions can potentially lead to new therapeutic approaches for PDAC liver metastasis and RA [1,4].

References:

1. Wang, Kun, He, Min, Fan, Xin, Dai, Chun, Zhang, Zixiang. 2023. SEMA5A-PLXNB3 Axis Promotes PDAC Liver Metastasis Outgrowth through Enhancing the Warburg Effect. In Journal of immunology research, 2023, 3274467. doi:10.1155/2023/3274467. https://pubmed.ncbi.nlm.nih.gov/36741230/

2. Su, Guomiao, Xu, Zifan, Liu, Shiyue, Li, Yanxi, Pan, Guoqing. 2024. Investigation of the Mechanism of SEMA5A and Its Associated Autophagy-Related Genes in Gastric Cancer. In International journal of general medicine, 17, 4101-4117. doi:10.2147/IJGM.S471370. https://pubmed.ncbi.nlm.nih.gov/39295854/

3. Nagy, Gergely N, Zhao, Xiao-Feng, Karlsson, Richard, Giger, Roman J, Jones, E Yvonne. 2024. Structure and function of Semaphorin-5A glycosaminoglycan interactions. In Nature communications, 15, 2723. doi:10.1038/s41467-024-46725-7. https://pubmed.ncbi.nlm.nih.gov/38548715/

4. Xiao, Chipeng, Lv, Chen, Sun, Siyuan, Wang, Jianguang, Yang, Xinyu. . TSP1 is the essential domain of SEMA5A involved in pannus formation in rheumatoid arthritis. In Rheumatology (Oxford, England), 60, 5833-5842. doi:10.1093/rheumatology/keab133. https://pubmed.ncbi.nlm.nih.gov/33616619/