The long-term goal of this project is to understand the molecular mechanisms by which retromer controls cellular processes during development. Retromer is an evolutionarily conserved multi-subunit complex, consisting of two complexes, the cargo recognition Vps26-Vps29- Vps35 heterotrimer and a membrane-targeting heterodimer or homodimer. Early studies in yeast and mammalian cell culture have demonstrated its roles in mediating endosome-Golgi trafficking of several proteins including mammalian cation-independent mannose-6-phosphate receptor. However, the roles of retromer complex in development have not been examined until recently. Our recent studies have uncovered an essential role of retromer complex in Wnt secretion. We showed that retromer is involved in endosome-to-Golgi transport of Wntless (Wls), a seven-pass transmembrane protein required for Wnt secretion. In the absence of retromer activity, Wls is unstable and is degraded, thereby causing Wnt secretion defects. Importantly, while retromer is not involved in many other developmental signaling pathways, we found that retromer is crucial for other two essential developmental processes including (1) the apicobasal polarity of epithelium during Drosophila embryogenesis and (2) hematopoeisis during larval development. Our preliminary studies have demonstrated that retromer regulates the trafficking of Crumbs (crb) to control the apicobasal polarity of epithelium, while it is involved in regulating Toll/Dorsal signaling pathway to control hematopoeisis. Thus, our studies have uncovered three essential roles of the retromer complex in development. In this application, we will further investigate the roles of retromer in Wnt secretion, in the apicobasal polarity control and in Toll/dorsal signaling pathway.
In Aim1, we will examine the roles of ubiquitination and retromer in regulating Wls stability and recycling.
In Aim2, we will examine whether retromer controls epithelium polarity by regulating Crumb trafficking and stability.
In Aim3, we will determine the mechanism by which retromer regulates Toll trafficking and signaling. Together, our proposed studies will provide new insights into the mechanisms by which retromer regulates Wnt secretion, epithelium polarity and Toll/dorsal signaling during development.
Retromer controls Wnt and Toll signaling pathways as well as epithelium polarity. These signaling pathways and cell biology processes are essential for embryonic development. Defects in Wnt and Toll signaling pathways as well as epithelium polarity are associated with many human diseases including cancers. The outcomes of this application will help understanding related human disease processes.
|Zhang, Xiujuan; Chen, Ying; Ye, Ying et al. (2017) Wnt signaling promotes hindgut fate commitment through regulating multi-lineage genes during hESC differentiation. Cell Signal 29:12-22|
|Wang, Guolun; Tang, Xiaofang; Chen, Yujie et al. (2014) Hyperplastic discs differentially regulates the transcriptional outputs of hedgehog signaling. Mech Dev 133:117-25|
|Huang, Q; Tang, X; Wang, G et al. (2014) Ubr3 E3 ligase regulates apoptosis by controlling the activity of DIAP1 in Drosophila. Cell Death Differ 21:1961-70|
|Zhou, Bo; Yun, Eun-Young; Ray, Lorraine et al. (2014) Retromer promotes immune quiescence by suppressing Spätzle-Toll pathway in Drosophila. J Cell Physiol 229:512-520|
|Zhang, Yan; You, Jia; Ren, Wenyan et al. (2013) Drosophila glypicans Dally and Dally-like are essential regulators for JAK/STAT signaling and Unpaired distribution in eye development. Dev Biol 375:23-32|
|Tang, Xiaofang; Wu, Yihui; Belenkaya, Tatyana Y et al. (2012) Roles of N-glycosylation and lipidation in Wg secretion and signaling. Dev Biol 364:32-41|
|You, Jia; Belenkaya, Tatyana; Lin, Xinhua (2011) Sulfated is a negative feedback regulator of wingless in Drosophila. Dev Dyn 240:640-8|
|Zhang, Peng; Wu, Yihui; Belenkaya, Tatyana Y et al. (2011) SNX3 controls Wingless/Wnt secretion through regulating retromer-dependent recycling of Wntless. Cell Res 21:1677-90|
|Zhou, Bo; Wu, Yihui; Lin, Xinhua (2011) Retromer regulates apical-basal polarity through recycling Crumbs. Dev Biol 360:87-95|