Control of symmetric cell division by the spindle assembly factor HMMR

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The growth and development of a tissue involves interaction between the cells in the tissue and their local environment, including the extracellular matrix (ECM). Cells in a tissue must balance growth with death and these two complex processes are controlled by cues provided by their environment. Hyaluronan is an ECM component that absorbs water in the tissue but also engages surface receptors on cells to promote their growth and movement. Due to its hydrating nature, hyaluronan has many commercial uses, including cosmetic applications, but it is also needed for the maintenance and differentiation of certain stem cells. Interestingly, we have found that hyaluronan mediated motility receptor (HMMR), one of few defined receptors for hyaluronan, is in fact a centrosome and microtubule-associated protein that regulates cell growth. Today, we do not fully know how HMMR regulates cell growth or how it might affect hyaluronan signaling. Moreover, we do not yet know if these potential functions are separate or connected. The long term goal for the proposed research program is to better understand the molecules and mechanisms that control cell division in stem cells. The short term goal for the proposed research is to determine the processes controlled by HMMR during cell growth. The overarching hypothesis is that HMMR regulates microtubule-based processes and is not needed for hyaluronan binding. To move towards the long term goal of our research program, this proposal outlines research methodologies that will address three specific objectives in the next five years: 1. Understand how HMMR regulates the way cells divide and the size of the progeny cells that are produced by each division. 2. Determine whether HMMR is needed as a receptor for hyaluronan to mediate signaling events. 3. Use mice that are deficient for Hmmr in a specific tissue to determine the need for HMMR during the growth of progenitor cells during tissue development and maintenance in vivo. The expertise in the Maxwell lab lies in our studies of HMMR and we have a number of unique models to study HMMR biology. We anticipate several benefits from the research program. We will determine the contributions of a putative receptor to a vital ECM component. In addition, we will generate molecular insights into the mechanisms by which tissue-specific stem cells divide and maintain the integrity of epithelial tissue.