Constitutive, mosaic expression of TIE2 p.L914F during mouse development causes formation of venous malformation

The hyperactivating p.L914F mutation in TIE2, a receptor tyrosine kinase that is essential for vascular development and function, has been found to drive sporadic venous malformation (VM). While germline or early developmental expression of the mutation is thought to be lethal, mosaic or somatic expression is expected to result in VM disease. However, this has never been shown experimentally. Therefore, we utilized a genetic murine model of TIE2 p.L914F to examine the effects of the mutation in the mosaic condition.

Using an mTmG reporter mouse, we show that the CMV-Cre mouse line drives mosaic Cre recombination during early embryonic development. We then crossed B6-Tg(Rosa26-TIE2 ^L914F ) ^EBos (TIE2 ^L914F ) mice to CMV-Cre mice, to drive mosaic expression of TIE2 p.L914F during development. The offspring of these mice did not have the expected Mendelian ratio of mutant to control animals, indicating that mutant mice experienced partial lethality during development. Furthermore, surviving CMV-Cre;TIE2^L914F mutant offspring developed a VM phenotype, with the formation of massively enlarged venous/capillary vessels in various tissues.

In this study, we show that mosaic embryonic expression of the VM-causative mutation TIE2 p.L914F causes partial embryonic lethality and the formation of a VM phenotype. This a novel in vivo model of mutant TIE2-driven VM disease and it illustrates that the extent of the mutational event during development will contribute to varying levels of severity in the VM phenotype.