Isthmin is a secreted protein, and it was initially identified in the Xenopus midbrain-hindbrain organizer (MHB) or isthmus organizer, where it is highly expressed. The MHB is an important signaling center in vertebrates and regulates the polarized morphological differentiation of the adjacent tectum and cerebellum. Mouse Isthmin is a 454 amino acid protein containing a Thrombospondin Type 1 Repeat (TSR) domain in the central region and an Adhesion-associated domain in MUC4 and Other Proteins (AMOP) domain at the C-terminal. The TSR domains are highly conserved with 98% identity between mouse and human, and 87-88% identity between mouse and Xenopus. The C-terminal AMOP domains are also highly conserved with 99% identity between mouse and human; and 91% identity between mouse and Xenopus. Mouse isthmin nucleotide sequence is similar to the human chromosome 20 open reading frame 82 (C20orf82). The Ism1 gene is conserved in human, chimpanzee, dog, cow, chicken, and zebrafish. Recently it has been suggested that isthmin has angiostatic activity in vitro and in vivo. Isthmin inhibits EC capillary network formation mainly by interfering with the early stages of in vitro angiogenesis on matrigel. Isthmin inhibits VEGF-induced EC proliferation and induces apoptosis in presence of VEGF. Over expression of Isthmin in B16 melanoma inhibits tumor growth and tumor angiogenesis in mice. Knockdown of isthmin in zebrafish embryos leads to abnormal intersegmental vessel (ISV) formation in the trunk.
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