Itga8, encoding the alpha 8 subunit of the heterodimeric integrin alpha8beta1, is crucial in maintaining the integrity of various tissues and is involved in numerous biological processes. It is known to play a role in cell adhesion, extracellular matrix (ECM) remodeling, and the regulation of cell signaling pathways, which are essential for normal development and tissue homeostasis [1-10]. Genetic models, such as knockout (KO) mouse models, have been instrumental in elucidating its functions.

The Itga8-CreER T2 mouse model has shown preferential activity in vascular smooth muscle cells (SMCs), enabling unfettered phenotyping of vascular SMCs following selective gene loss. For example, Itga8-CreER T2-mediated knockout of serum response factor (Srf) yields viable mice without intestinal pathology, unlike Myh11-CreER T2-mediated Srf knockout [1]. In another study, Itga8-Cre-mediated deletion of YAP and TAZ in adult mice impairs bladder contractility with minimal inflammation and chondrogenic differentiation, suggesting that YAP and TAZ regulate myocardin expression in the detrusor, which is important for SMC differentiation and contractility [2]. In vascular SMC-specific YAP/TAZ knockout (using Itga8-Cre mouse model), mice spontaneously develop aneurysms, characterized by elastin disarray, SMC apoptosis, and proteoglycan accumulation [9]. ITGA8-positive cells in the conventional outflow tissue exhibit Schlemm's canal endothelial cell properties, implicating a role of ITGA8 in aqueous humor outflow resistance regulation [3]. Bi-allelic pathogenic variants in ITGA8 cause slowly progressive renal disease, broadening the clinical and genotypic spectrum of ITGA8 defects [5]. Hypermethylated ITGA8 facilitates bladder cancer cell proliferation and metastasis, and 5-Aza-dC treatment inhibits these processes by decreasing ITGA8 methylation levels [6]. ITGA8 expression is significantly upregulated in fibrotic liver tissues, and silencing ITGA8 in hepatic stellate cells attenuates CCl4-induced liver fibrosis via suppression of COL11A1 [8]. In lung adenocarcinoma, ITGA8 expression is related to prognosis, immune cell infiltration, and cancer stemness, and is regulated by the LINC01798/miR-17-5p axis [7]. Also, M2 macrophage-derived exosomal circTMCO3 enhances ovarian cancer malignancy through the miR-515-5p/ITGA8 axis [4].

In conclusion, Itga8 is essential for maintaining tissue integrity and normal physiological functions in various organs. KO and conditional knockout (CKO) mouse models have been key in revealing its role in diseases such as vascular disorders, bladder dysfunction, kidney diseases, and cancers. These findings provide valuable insights into the underlying mechanisms of these diseases and suggest potential therapeutic targets related to Itga8.