Plxnd1, also known as plexin D1, is a cell-surface receptor of the semaphorin family. It is involved in multiple biological processes such as axon guidance, mechanosensation, and embryonic development including neurogenesis and vasculogenesis. It is associated with pathways like the PI3K/AKT-signaling pathway [3].

In mice, knockdown of SEMA3D (a ligand for PLXND1) in pancreatic ductal adenocarcinoma (PDA) cells or disruption of PlxnD1 in peripheral sensory neurons reduces innervation of orthotopic PDAs and metastasis [1]. In atrial fibrillation model mice, increased PLXND1 expression in endocardial endothelial cells leads to calcium dyshomeostasis, inhibiting autophagy flux and resulting in cell dysfunction [2]. In colorectal cancer, PLXND1-knockdown decreases cell migration and invasion, and in vivo experiments show it suppresses epithelial-mesenchymal transition (EMT) [3]. In zebrafish and human endothelial cell models, Plxnd1 is crucial for controlling the caliber of the Dorsal Aorta via the transcription factor Klf2 [4]. In endothelial cells, PLXND1 is a direct force sensor regulating atherosclerotic lesion distribution [5]. Plxnd1 knockout mice exhibit severe heart and lung defects related to anomalous pulmonary venous return (APVR) [6]. Knockdown or knockout of PLXND1 in treatment-resistant prostate cancer inhibits neural lineage pathways, suppressing cell proliferation and tumor growth [7].

In conclusion, Plxnd1 plays essential roles in axon guidance, cardiovascular development, cancer metastasis, and autophagy regulation. Gene knockout and knockdown mouse models have significantly contributed to understanding its functions in diseases such as pancreatic cancer, atrial fibrillation, colorectal cancer, anomalous pulmonary venous return, and treatment-resistant prostate cancer, providing potential therapeutic targets for these diseases.