Role of AMOTL2 in developmental and pathological lymphangiogenesis

Abstract

Lymphatic system is a major vascular network of the body which regulates intestitial fluid, delivers lymphocytes during immune response and fat absorption in digestive system. However, research about the mechanism and molecular regulation of lymphangiogenesis in both development and pathological conditions are limited. Angiomotin-like-2 (AMOTL2) is a member of Motin family which consists Angiomotin, Angiomotin-like-1, and Angiomotin-like-2. Angiomotin-like-2 has been studied in various cell contexts including angiogenesis, epithelial cell arrangement, and cancer. The role of AMOTL2 in angiogenesis was studied for a long time, but in lymphatic vessels, no research was conducted regarding the contribution of AMOTL2. In this study, we examined the role of AMOTL2 in sprouting lymphangiogenesis in both developmental and pathological contexts. The depletion of AMOTL2 leads to impairment in sprouting lymphangiogeneis in embryos, and in several other pathological models. Interestingly, deletion of AMOTL2 also induces inactivation of ERK signaling which is known to participate in lymphangiognesis. To further understand the underlying mechanism, single cell RNA sequencing analysis of embryonic dorsal skin lymphatic endothelial cells was conducted and revealed the downregulation of transcription of ERK downstream genes. Our results suggest a novel mechanism of AMOTL2 regulating sprouting lymphangiognesis through MAPK-ERK signaling, and contribute the new potential target for therapeutic intervention.