Mechanisms of membrane ratcheting during cell intercalation The ability of cells in epithelial sheets to under neighbor cell rearrangements is essential to tissue shaping as well as repair and homeostasis mechanisms. In the Drosophila embryonic epithelium, individual cells are able to either consolidate cell-cell contacts or direct neighbor exchange movements through the contraction of vertical T1 interfaces and the subsequent resolution of horizontal T3 interfaces. A recent appreciation has been that changes in these topological relationships occur in response to pulses of actomyosin activity; however, the mechanism by which cell shape changes are maintained after contractile periods has been unclear. Here, we explore the function of a membrane-dependent cell shape ratcheting mechanism. We examine how the ratcheting mechanism is initiated by small GTPase GEF activity, and how this activity can be linked to plasma membrane dynamics. We will determine the function of PtdIns lipids in GEF recruitment and early morphogenesis, and identify the PtdIns phospho-species and PtdIns kinases that localize membrane ratcheting. We will further identify the relative roles of actomyosin networks and endocytic pathways in the termination and consolidation of ratcheting events, and the degree of coordination between these processes. Finally, the membrane trafficking pathways that are active in epithelial cells during gastrulation movements will be examined, and the function of recycling and endosomal pathways in driving interface contraction and growth will be determined. The proposed work will be a highly interdisciplinary project driven by a combination of quantitative analysis of experimental live-cell imaging data with physical and genetic manipulation of these processes. The results are expected to yield a comprehensive mechanistic insight into how cytoskeletal force generation is coupled with targeted remodeling of the plasma membrane to drive changes in cell shapes and topologies.
Epithelial tissues, such as the human skin and gut, maintain an essential barrier function, and the loss of this function is associated with the metastasis of many epithelial cancers. However, as cells age and need to be replaced, new cells must insert into the epithelial sheet in such a way as to maintain polarized barrier function. The intention of the proposed study is to examine the processes that direct dynamic epithelial cell rearrangements, thus leading to a better understanding of how the critical tissue integrity of epithelial tissues is maintained and how it may be disrupted by disease.
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