Our lab studies the morphogenesis of epithelia – the cells/tissues that cover our body and line our internal organs. We concentrate on two highly proliferative tissues, the skin and the intestine. Both of these tissues turn over rapidly throughout adulthood, contain stem cells that contribute to tissue homeostasis and both are common sites for cancer development. However, they have very different functions (skin forms a barrier, while the intestine absorbs nutrients) and very different morphologies. We want to understand how both cell shape and three-dimensional organization of cells is achieved to meet these diverse functions. The lab studies several basic questions related to the development and morphogenesis of these epithelia.
1. Spindle Orientation/Asymmetric Cell Division
Regulation of spindle orientation is used in many tissues to generate cell fate diversity through asymmetric cell divisions as well as to promote proper tissue architecture. The skin uses these divisions to stratify the epidermis, specify stem cells and form hair follicles. Our lab studies the cell biology of how mitotic spindle positioning is controlled, how these divisions are regulated developmentally and the consequences of loss of spindle orientation on tissue development, homeostasis and tumor formation.
2. Regulation of Centrosomes and Microtubule Organization
As cells differentiate they change their shape and the organization of their internal cytoskeleton, including microtubules. We are studying how non-centrosomal microtubule arrays are formed in cells, using genetics to understand the functions of these arrays, and determining how differentiation signals impact the composition and function of centrosomes and microtubules.
3. Cell-cell Adhesion
We study cell adhesion structures including adherens junctions, tight junctions and desmosomes and their interplay with underlying cytoskeletal structures. We are particularly interested in functions of the desmosome and how these are disrupted under disease conditions such as pemphigus.
4. Morphogenesis of the Intestinal Stem Cell Niche
Adult intestinal stem cells reside in a niche called the crypt. Newborn mice lack crypts and they develop over the first few weeks of life. We are using unbiased approaches to define the maturation and morphogenesis of crypt progenitor cells, performing quantitative morphometric analysis of the process, and developing mouse strains for the visualization and perturbation of crypt development.
Our studies are multi-disciplinary and span from mouse genetics to in vitro reconstitution experiments. This allows us not only to understand molecular mechanisms and dynamics, but also to understand the physiological consequence when they are disrupted in an animal. Using conditional knockout and transgenic technology, we can both observe the morphogenetic process in living animals/tissues and understand its molecular basis. A combination of live cell and animal imaging, cell biology, organ culture, mouse genetics and biochemistry are used to address these problems.