The long-term goal of this application is an understanding of the mechanisms of early lens development. We will build on our recent progress in understanding the genetics and signaling of lens induction by extending into the area of lens morphogenesis (defined as the epithelial shape changes that are critical features of lens development from the stage of the lens placode to the lens vesicle).
Our specific aims for the ongoing application are designed to address the question of how lens development signaling and morphogenesis are coordinated. In particular, our preliminary evidence has shown that N-cadherin has a critical function in lens formation. N-cadherin is an adhesion molecule that mediates epithelial adhesion and morphogenesis through a C-terminal connection to the actin cytoskeleton. N-cadherin is also very interesting because it has the ability to activate or enhance FGF signaling. We will investigate N-cadherin function by:
Aim 1, determining which source(s) of N-cadherin, presumptive lens ectoderm and/or presumptive retina is critical for lens induction, Aim 2, using molecular epistasis analysis to place N-cadherin within the existing genetic pathway for lens induction, Aim 3, determining why N-cadherin is required for lens induction by assessing its role in adhesion, morphogenesis and FGF pathway signaling. Investigation of N-cadherin function in lens induction is an interesting developmental problem, and clearly, an understanding of the basic mechanisms of lens development can provide an indication of future directions for therapeutic resolution of lens disease. However, in addition, it has recently been shown that N-cadherin can contribute to the metastatic behavior of tumor cells. From this point of view, our studies will also enhance our ability to plan therapies for the treatment of cancer.
|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|
|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; Küspert, Melanie et al. (2014) Stem cell factor Sox2 and its close relative Sox3 have differentiation functions in oligodendrocytes. Development 141:39-50|
|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|
|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|
|Choi, Yeon Sook; Zhang, Yuhang; Xu, Mingang et al. (2013) Distinct functions for Wnt/?-catenin in hair follicle stem cell proliferation and survival and interfollicular epidermal homeostasis. Cell Stem Cell 13:720-33|
|Ponferrada, Virgilio G; Fan, Jieqing; Vallance, Jefferson E et al. (2012) CRIM1 complexes with ß-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|
|Lin, Shuei-Liong; Li, Bing; Rao, Sujata et al. (2010) Macrophage Wnt7b is critical for kidney repair and regeneration. Proc Natl Acad Sci U S A 107:4194-9|
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