Unraveling the Wnt secretion pathway

Abstract

The Wnt family of signaling proteins has essential functions in development and adult tissue homeostasis throughout the animal kingdom. Although signaling cascades triggered by Wnt proteins have been extensively studied, much remains to be learned about how Wnts are produced and secreted and how their activity is regulated. Over the past few years it has become clear that the secretion of Wnt proteins requires a specialized trafficking pathway. A central player in this is the Wnt sorting receptor Wntless, which escorts the Wnt from the Golgi to the plasma membrane. In order to efficiently secrete Wnts, Wntless has to be retrieved to the Golgi for a novel round of Wnt secretion. The Wntless transport from endosomes to Golgi requires the activity of retromer complex. In this thesis we identified and describe several new component, which are required for efficient Wnt secretion. These play important roles in the retromer dependent endosome to Golgi traffic of Wntless. One of these component, snx-3, associates with the retromer and defines an alternative retromer retrieval pathway. Finally we have used an adapted fluorescent in situ labeling protocol to carefully examine the Wnt expression in the nematode C. elegans at the single transcript level. Additionally, we included the only secreted Wnt inhibitor of the SFRP family, sfrp-1. We found that the Wnts are mostly expressed in the posterior whereas the inhibitor is anteriorly expressed. We found that the inhibitor is important to suppress several Wnts for correct migration of several neuroblasts along the anteroposterior axis. Altogether this suggests that opposing activities of Wnts and Wnt inhibitor patter the anteroposterior axis.