Wnt pathways in lens polarity Wnt pathways are known to have a critical role in many aspects of development and disease. The long term goal of this competitive renewal application is an understanding of the role of Wnt pathways in regulating the epithelial to fiber cell transition and lens polarity during development. Preliminary studies show that when production of Wnt ligands is eliminated in the lens lineage, remarkably, lens epithelial cells differentiate into lens fiber cells. By contrast, when the Wnt pathway transcription factor Tcf3 is deleted conditionally in early lens, there is an opposite response where fiber cells fail to differentiate. These are surprising findings that underscore the importance of the Wnt/2-catenin pathway for regulating lens development and establishing the anterior epithelium-posterior fiber cell pattern that defines lens polarity. The function of this pathway in lens development has important implications for lens biology and perhaps for pathophysiologies where the epithelium is not maintained. Our central hypothesis is that The Wnt/2-catenin pathway regulates the epithelial-to-fiber cell transition to establish lens polarity. To investigate the validity of this hypothesis, we propose three Aims. 1. To determine the source of Wnt ligands crucial for establishing lens polarity. The mouse Wntless allele we have generated is very valuable because it is required for the activity of all Wnt ligands and thus solves the problem of how to generate a ligand loss-of-function when multiple ligands are expressed. We will take advantage of this allele, combined with different cre recombinase lines, to identify the source, or sources of Wnt ligands critical for the epithelial-to-fiber cell transition and lens polarity. 2. To determine whether non-canonical Wnt ligands provide negative-feedback regulation of the lens epithelial Wnt response. It has recently been shown that some Wnt ligands function only in the non-canonical pathways and furthermore, that they can block Wnt/2-catenin signaling by preventing the association of the Lrp5/6 co-receptors with Frizzleds. When coupled with the observation that several non-canonical ligands are expressed in lens fiber cells, this suggests that they may serve to down-regulate Wnt/2-catenin signaling after fiber cells have made contact with the epithelium. 3: To determine whether lens repolarization requires reactivation of the canonical Wnt pathway. In 1963, Coulombre and Coulombre performed the now classical experiment showing that a reversed chick lens (epithelium facing the retina) would re-polarize over the course of 10 days. As shown in our preliminary data, disruption of the Wnt pathway disrupts lens polarity suggesting that the Wnt pathway may be re-activated during re-polarization. We will test this hypothesis by monitoring and modulating the Wnt pathway during chick lens re-polarization. Combined, these studies will provide an in- depth assessment of the role of the Wnt pathway in lens development and overall, an important step forward in our understanding of this unique organ.
In this application, we propose the study a cell-cell signaling pathway, the so-called Wnt pathway that is known to be critical for embryonic development, for tissue homeostasis and for the development of tumors. We will determine whether the Wnt pathway is responsible for determining the orientation of the lens within the eye and thus, whether this pathway is important for the unique optical capability of this organ.
|Carpenter, April C; Smith, April N; Wagner, Heidi et al. (2015) Wnt ligands from the embryonic surface ectoderm regulate 'bimetallic strip' optic cup morphogenesis in mouse. Development 142:972-82|
|Chauhan, Bharesh; Plageman, Timothy; Lou, Ming et al. (2015) Epithelial morphogenesis: the mouse eye as a model system. Curr Top Dev Biol 111:375-99|
|Goodnough, L Henry; Dinuoscio, Gregg J; Ferguson, James W et al. (2014) Distinct requirements for cranial ectoderm and mesenchyme-derived wnts in specification and differentiation of osteoblast and dermal progenitors. PLoS Genet 10:e1004152|
|Lang, Richard A; Herman, Ken; Reynolds, Albert B et al. (2014) p120-catenin-dependent junctional recruitment of Shroom3 is required for apical constriction during lens pit morphogenesis. Development 141:3177-87|
|Hoffmann, Stephanie A; Hos, Deniz; KÃ¼spert, Melanie et al. (2014) Stem cell factor Sox2 and its close relative Sox3 have differentiation functions in oligodendrocytes. Development 141:39-50|
|Choi, Yeon Sook; Zhang, Yuhang; Xu, Mingang et al. (2013) Distinct functions for Wnt/Î²-catenin in hair follicle stem cell proliferation and survival and interfollicular epidermal homeostasis. Cell Stem Cell 13:720-33|
|Katayama, Kei-ichi; Imai, Fumiyasu; Campbell, Kenneth et al. (2013) RhoA and Cdc42 are required in pre-migratory progenitors of the medial ganglionic eminence ventricular zone for proper cortical interneuron migration. Development 140:3139-45|
|Ponferrada, Virgilio G; Fan, Jieqing; Vallance, Jefferson E et al. (2012) CRIM1 complexes with ÃŸ-catenin and cadherins, stabilizes cell-cell junctions and is critical for neural morphogenesis. PLoS One 7:e32635|
|Plageman Jr, Timothy F; Lang, Richard A (2012) Generation of an Rx-tTA: TetOp-Cre knock-in mouse line for doxycycline regulated Cre activity in the Rx expression domain. PLoS One 7:e50426|
|Carpenter, April C; Rao, Sujata; Wells, James M et al. (2010) Generation of mice with a conditional null allele for Wntless. Genesis 48:554-8|
Showing the most recent 10 out of 20 publications