Sema5a, or Semaphorin-5A, is a gene with multifaceted functions. It is a bifunctional guidance cue in neurons, interacting with heparan sulfate (HS) and chondroitin sulfate (CS) glycosaminoglycans (GAGs) to regulate axon guidance. In the context of disease, it has been implicated in various pathways related to cancer and neurological disorders [2].

In pancreatic adenocarcinoma (PDAC), M2 type tumor-associated macrophages (TAMs) secrete Sema5A, which binds to its receptor PLXNB3 on tumor cells. This Sema5A-PLXNB3 axis promotes tumor cell proliferation and outgrowth in liver metastasis by enhancing the Warburg effect [1]. In rheumatoid arthritis (RA), Sema5A expression is increased, and it promotes fibroblast-like synoviocytes (FLSs) proliferation and angiogenesis. The TSP1 domain of Sema5A is essential for pannus formation in RA, as demonstrated in Sema5a-/-CIA mice [4]. In infantile spasms, a novel damaging de novo mutation in Sema5A was identified, and gene-function analysis showed its involvement in axonal, neuronal, and synapse-associated processes [3].

In summary, Sema5a plays crucial roles in both normal neuronal development through axon guidance and in disease-related processes such as cancer metastasis and autoimmune diseases. Gene knockout mouse models, like the Sema5a-/-CIA mice, have been instrumental in revealing its role in specific disease conditions, helping to understand the underlying molecular mechanisms and potentially guiding the development of targeted therapies.