Extl2-KO Mouse

EXTL2, an N-acetylhexosaminyltransferase-encoding gene, is one of the three EXT-like genes in the human genome homologous to EXT1 and EXT2. It plays a role in glycosaminoglycan (GAG) biosynthesis. Specifically, it can transfer a GlcNAc residue to the phosphorylated tetrasaccharide linkage region by xylose kinase 1 (FAM20B), terminating GAG chain elongation [1,3]. This indicates its importance in regulating GAG biosynthesis and associated pathways [1,3]. Gene-knockout mouse models have been crucial in studying EXTL2's functions [1,3,4,5].

In EXTL2-knockout mice, GAG production is significantly higher than in wild-type mice [1,3]. Under carbon tetrachloride-induced liver failure, hepatocyte proliferation and liver regeneration are impaired in EXTL2-knockout mice due to reduced hepatocyte-growth-factor-mediated signaling [1,5]. In a model of chronic kidney disease, matrix mineralization in vascular smooth muscle cells of EXTL2-knockout mice is enhanced, as altered GAG biosynthesis affects bone-morphogenetic-protein signaling, promoting the differentiation of these cells into osteoblasts [1]. Also, in a demyelinating injury model, EXTL2-knockout mice had excessive CSPG deposition, exacerbated axonal damage, and increased microglia/macrophages in lesions [2]. Additionally, in the context of non-alcoholic steatohepatitis and hepatocarcinoma, GAGs produced without EXTL2 act as DAMPs, signaling via Toll-like 4 receptor and contributing to inflammation-driven tumor promotion [4].

In conclusion, EXTL2-mediated regulation of GAG biosynthesis is vital for maintaining tissue homeostasis under pathological conditions. Studies using EXTL2-knockout mouse models have revealed its role in various disease-related processes, including liver regeneration, aortic calcification, neuroinflammation, and liver tumorigenesis. Understanding EXTL2's functions provides insights into the mechanisms underlying these diseases and may offer potential therapeutic targets [1,2,4,5].

References:

1. Nadanaka, Satomi, Kitagawa, Hiroshi. 2013. EXTL2 controls liver regeneration and aortic calcification through xylose kinase-dependent regulation of glycosaminoglycan biosynthesis. In Matrix biology : journal of the International Society for Matrix Biology, 35, 18-24. doi:10.1016/j.matbio.2013.10.010. https://pubmed.ncbi.nlm.nih.gov/24176719/

2. Pu, Annie, Mishra, Manoj K, Dong, Yifei, Sawcer, Stephen, Yong, V Wee. 2020. The glycosyltransferase EXTL2 promotes proteoglycan deposition and injurious neuroinflammation following demyelination. In Journal of neuroinflammation, 17, 220. doi:10.1186/s12974-020-01895-1. https://pubmed.ncbi.nlm.nih.gov/32703234/

3. Nadanaka, Satomi, Zhou, Shaobo, Kagiyama, Shoji, Asano, Masahide, Kitagawa, Hiroshi. 2013. EXTL2, a member of the EXT family of tumor suppressors, controls glycosaminoglycan biosynthesis in a xylose kinase-dependent manner. In The Journal of biological chemistry, 288, 9321-33. doi:10.1074/jbc.M112.416909. https://pubmed.ncbi.nlm.nih.gov/23395820/

4. Nadanaka, Satomi, Hashiguchi, Taishi, Kitagawa, Hiroshi. 2020. Aberrant glycosaminoglycan biosynthesis by tumor suppressor EXTL2 deficiency promotes liver inflammation and tumorigenesis through Toll-like 4 receptor signaling. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 34, 8385-8401. doi:10.1096/fj.201902076R. https://pubmed.ncbi.nlm.nih.gov/32347583/

5. Nadanaka, Satomi, Kagiyama, Shoji, Kitagawa, Hiroshi. . Roles of EXTL2, a member of the EXT family of tumour suppressors, in liver injury and regeneration processes. In The Biochemical journal, 454, 133-45. doi:10.1042/BJ20130323. https://pubmed.ncbi.nlm.nih.gov/23734945/