Dorsal closure in Drosophila is a key model system for cell sheet movements during development and wound healing. During closure two sheets of lateral epidermis advance to close a dorsal opening. Forces for closure are produced by a unique array of actomyosin in the leading edges of each sheet of lateral epidermis and by two distinct arrays of actomyosin in the amnioserosa, which fills the dorsal opening. Supra-cellular actomyosin rich purse strings (PSs) provide tension in the leading edges (leading edge cells oscillate during the bulk of closure, then shorten as they are zipped into the canthi). In the amnioserosa, junctional belts (JBs) and apical medial arrays (AMAs) drive both oscillations in cell shape and then ingression when individual cells apically constrict and drop out of the plane of the amnioserosa. This proposal focuses on how these actomyosin arrays generate force, how force generation is regulated and on identifying the molecular players that characterize the cells that contribute to both processes. We use high-resolution confocal imaging of genetically encoded fluorophore-fusions in living embryos coupled with laser surgical, mechanical jump protocols to interrogate mutant, drug-treated and wildtype specimens. Confocal images are segmented and digitally analyzed. Biophysical reasoning is used to develop quantitative models that describe our results, make testable hypotheses and refine models for further rounds of experiment and analysis. We also implement new candidate and systems approaches to identify the molecular players that characterize the cells that contribute to closure. We seek answers to key extant questions about dorsal closure and morphogenesis in other cell sheets: How are forces produced at the cell and molecular level? How are such forces regulated? Which transcripts/proteins are present in the cells that drive closure? These studies are at the next frontier in understanding morphogenesis in dorsal closure and in the myriad of other systems that require apical constrictions for powering changes in cell sheet morphology.

Public Health Relevance

This work focuses on dorsal closure, a process in the fruit fly Drosophila melanogaster that models cell sheet movements in vertebrates and humans. Drosophila offers unique opportunities for multidisciplinary approaches and many of the proteins involved in movement are highly conserved between flies and humans (some are >90% identical and many human proteins can experimentally rescue genetic defects in their fly counterparts). These studies in Drosophila provide insight into the molecular and cellular basis of the motility that underlies cell sheet movements in human development and the programmed interplay between cells that goes awry when human cells become metastatic and cancerous. ! !

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
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Nie, Zhongzhen
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Duke University
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Mortensen, Richard D; Moore, Regan P; Fogerson, Stephanie M et al. (2018) Identifying Genetic Players in Cell Sheet Morphogenesis Using a Drosophila Deficiency Screen for Genes on Chromosome 2R Involved in Dorsal Closure. G3 (Bethesda) 8:2361-2387
Lo, Wei-Chang; Madrak, Craig; Kiehart, Daniel P et al. (2018) Unified biophysical mechanism for cell-shape oscillations and cell ingression. Phys Rev E 97:062414
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Lu, Heng; Sokolow, Adam; Kiehart, Daniel P et al. (2016) Quantifying dorsal closure in three dimensions. Mol Biol Cell 27:3948-3955
Marston, Daniel J; Higgins, Christopher D; Peters, Kimberly A et al. (2016) MRCK-1 Drives Apical Constriction in C. elegans by Linking Developmental Patterning to Force Generation. Curr Biol 26:2079-89
Goldstein, Bob; Kiehart, Daniel P (2015) Moving Inward: Establishing the Mammalian Inner Cell Mass. Dev Cell 34:385-6
Lu, Heng; Sokolow, Adam; Kiehart, Daniel P et al. (2015) Remodeling Tissue Interfaces and the Thermodynamics of Zipping during Dorsal Closure in Drosophila. Biophys J 109:2406-17

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