Ext1-KO Mouse

Ext1, also known as Exostosin 1, is an endoplasmic reticulum-resident transmembrane glycosyltransferase. It plays a crucial role in endoplasmic reticulum (ER) homeostasis. Ext1 is involved in the biosynthesis and distribution of heparan sulfate, which is associated with multiple cellular functions and signaling pathways [2,4]. Loss-of-function mutations in Ext1 are linked to hereditary multiple exostosis (HME), highlighting its importance in normal biological processes [2,6].

In the context of diseases, in non-alcoholic fatty liver disease (NAFLD), high-fat-diet induced mice show decreased hepatic Ext1 expression. Ext1 deficiency promotes free fatty acid (FFA)-induced insulin resistance in hepatocytes and exacerbates ER stress-triggered autophagy disruption, accelerating NAFLD progression [2].

In membranous lupus nephritis, EXT1-positive patients had better kidney function at diagnosis compared to EXT1-negative patients, and EXT1 status may change during the disease course [1]. Also, a subset of membranous nephropathy is associated with accumulation of EXT1 in the glomerular basement membrane, and autoimmune disease is common in this group [3].

In acute lymphoblastic leukemia (ALL), EXT1 expression is downregulated, and low bone marrow EXT1 levels independently predict poor prognoses. EXT1 promotes cell apoptosis via deactivating the ERK1/2 pathway, and miR-665 can suppress EXT1 to promote cell growth and inhibit apoptosis [4].

In non-small cell lung carcinoma, EXT1 methylation promotes proliferation and migration via the WNT signalling pathway and predicts a poor prognosis [5].

In conclusion, Ext1 is essential for maintaining ER homeostasis and is involved in the biosynthesis of heparan sulfate. Studies using various models, though not always knockout mouse models, have revealed its significance in diseases such as NAFLD, membranous nephropathy-related conditions, ALL, and non-small cell lung carcinoma. These findings help in understanding the biological functions of Ext1 and provide potential insights for disease treatment and prevention.