The Mechanism And Function Of TMEM198in Activating Wnt Signaling

Wnt signaling plays important roles not only in embryonic development but also innormal physiological processes of adult. Dysregulation of Wnt signaling would causespecific developmental defects and human diseases including certain kinds of cancer.Here we investigated the function and mechanism of a novel transmembraneprotein TMEM198, which is conserved from Drosophila to human. Results in culturecells indicated that TMEM198is able to specifically co-operate with LRP6, theco-receptor, to activate canonical Wnt signaling via promoting LRP6phosphorylationand aggregation. Mechanistically, TMEM198promotes LRP6aggregation through itstransmembrane domains, and its carboxyl terminus is responsible for recruiting Caseinkinase1. Using both strategies, TMEM198ensures LRP6phosphorylation andconsequent Wnt signal activation. Our studies also demonstrate that TMEM198ispartially required for canonical Wnt signaling as well as Casein kinase1-mediatedLRP6phosphorylation. In Xenopus embryos, TMEM198is also able to activate LRP6.Knockdown TMEM198by micro-injection of antisense Morpholino oligos resultedembryos with less pigmentation, smaller eyes and bent axis. The expression of En2(midbrain-hindbrain boundary marker) and Sox10/Sox9(neural crest markers) wassignificantly reduced. These results suggested that TMEM198is required for Wnt-mediated neural patterning during Xenopus embryogenesis.Together, our work has uncovered a function of the previously uncharacterizedtransmembrane protein family and introduced a new component to the Wnt signalingpathway. Our work also provided the first potential regulator for Casein kinases duringLRP6phosphorylation. In general, this study has deepened our understanding of bothWnt signaling transduction as well as neural patterning during Xenopus embryogenesis.