Tie1-flox Mouse

Tie1, or Tyrosine kinase with immunoglobulin and EGF-like domains 1, is an endothelial cell-specific orphan receptor. It plays crucial roles in angiogenesis, lymphangiogenesis, and the development of the cardiovascular system. Tie1 modulates signaling pathways such as Angiopoietin/Tie2 signaling, and its associated pathways are involved in processes like cell migration, proliferation, and vessel morphogenesis [4,5,6,7]. Genetic models, including gene-knockout mouse models, have been instrumental in studying its functions.

In liver fibrosis, LECT2, a ligand of Tie1, interrupts Tie1/Tie2 heterodimerization, facilitating Tie2/Tie2 homodimerization, activating PPAR signaling, and inhibiting endothelial cell migration and tube formation. LECT2 overexpression in vivo inhibits portal angiogenesis, promotes sinusoid capillarization, and worsens fibrosis, while these changes are reversed in Lect2-KO mice [1]. In cervical cancer, TIE1 overexpression promotes cell proliferation, migration, invasion in vitro and tumor growth and metastasis in vivo, interacting with Basigin to stimulate the Basigin-matrix metalloproteinase axis [2]. In primary open-angle glaucoma, increased genetically proxied TIE1 signaling is associated with a reduction in intraocular pressure [3]. In zebrafish, tie1 mutant embryos display reduced endothelial and endocardial cell numbers, reduced heart size, and cardiac defects, with down-regulation of tll1, and tll1 overexpression can partially rescue these phenotypes [4]. In mice, TIE1 deficiency disrupts venous integrity, leading to increased sprouting angiogenesis and vascular bleeding, and TIE1 and TIE2 act synergistically with COUP-TFII to restrict sprouting angiogenesis during venous system development [5]. Loss-of-function mutations of TIE1 in humans and homozygous mouse models cause lymphatic dysfunction and edema, emphasizing the role of the ANGPT2/TIE1 pathway in lymphatic function [6]. In zebrafish, Angpt1 binds to Tie1 as a ligand, and Angpt1/Tie1 signaling is essential for lymphatic development, functioning in endothelial cell migration, proliferation, and lymphatic specification [7].

In conclusion, Tie1 is essential for multiple biological processes including angiogenesis, lymphangiogenesis, and cardiovascular development. Model-based research, especially KO mouse models, has revealed its role in various disease conditions such as liver fibrosis, cervical cancer, primary open-angle glaucoma, and lymphatic-related disorders, providing potential therapeutic targets for these diseases.