Dynamics of cell polarity in tissue morphogenesis: A comparative view from Drosophila and Ciona [version 1; referees: 2 approved]

Citation: Veeman, M. T., & McDonald, J. A. (2016). Dynamics of cell polarity in tissue morphogenesis: A comparative view from Drosophila and Ciona [version 1; referees: 2 approved]. F1000Research, 5. doi:10.12688/F1000RESEARCH.8011.1Tissues in developing embryos exhibit complex and dynamic rearrangements that shape forming organs, limbs, and body axes. Directed migration, mediolateral intercalation, lumen formation, and other rearrangements influence the topology and topography of developing tissues. These collective cell behaviors are distinct phenomena but all involve the fine-grained control of cell polarity. Here we review recent findings in the dynamics of polarized cell behavior in both the Drosophila ovarian border cells and the Ciona notochord. These studies reveal the remarkable reorganization of cell polarity during organ formation and underscore conserved mechanisms of developmental cell polarity including the Par/atypical protein kinase C (aPKC) and planar cell polarity pathways. These two very different model systems demonstrate important commonalities but also key differences in how cell polarity is controlled in tissue morphogenesis. Together, these systems raise important, broader questions on how the developmental control of cell polarity contributes to morphogenesis of diverse tissues across the metazoa. © 2016 Veeman MT and McDonald JA

Dynamic myosin activation promotes collective morphology and migration by locally balancing oppositional forces from surrounding tissue

Citation: Aranjuez, G., Burtscher, A., Sawant, K., Majumder, P., & McDonald, J. A. (2016). Dynamic myosin activation promotes collective morphology and migration by locally balancing oppositional forces from surrounding tissue. Molecular Biology of the Cell, 27(12), 1898-1910. doi:10.1091/mbc.E15-10-0744Migrating cells need to overcome physical constraints from the local microenvironment to navigate their way through tissues. Cells that move collectively have the additional challenge of negotiating complex environments in vivo while maintaining cohesion of the group as a whole. The mechanisms by which collectives maintain a migratory morphology while resisting physical constraints from the surrounding tissue are poorly understood. Drosophila border cells represent a genetic model of collective migration within a cell-dense tissue. Border cells move as a cohesive group of 6-10 cells, traversing a network of large germ line-derived nurse cells within the ovary. Here we show that the border cell cluster is compact and round throughout their entire migration, a shape that is maintained despite the mechanical pressure imposed by the surrounding nurse cells. Nonmuscle myosin II (Myo-II) activity at the cluster periphery becomes elevated in response to increased constriction by nurse cells. Furthermore, the distinctive border cell collective morphology requires highly dynamic and localized enrichment of Myo-II. Thus, activated Myo-II promotes cortical tension at the outer edge of the migrating border cell cluster to resist compressive forces from nurse cells. We propose that dynamic actomyosin tension at the periphery of collectives facilitates their movement through restrictive tissues

A Screen for Genetic Modifiers of Protein Phosphatase 1 Function in Drosophila Collective Cell Cohesion and Migration

Cells can migrate collectively in tightly or loosely-associated groups during tissue and organ formation, during embryonic development, in tumor metastases, and in wound healing. Drosophilaborder cellsserve as an excellent genetic model of collective cell migration inside a developing tissue. During ovarian development, 6-8 cells form the border cell cluster and migrate together as a cohesive group to reach the large oocyte. Previous experiments have shown that Nuclear inhibitor of Protein Serine Threonine Phosphatase 1 (NiPP1) causes border cells to separate into single cells, rather than stay in a group, and limits their ability to migrate. NiPP1 inhibits the activity of the Protein Phosphatase 1 (PP1) enzyme. Therefore, overexpressing NiPP1, though a modifier screen, will allows us identify genes that work with PP1 to promote the adhesion and collective migration of border cells. To carry out this genetic screen, females expressing NiPP1 in border cells are crossed to a collection of mutant strains, called deficiencies, that remove a number of genes. Ovaries from the resulting progeny are assayed for cohesion and migration of the border cell cluster by fluorescent microscopy. In this project, larger deficiencies have been shown to suppress (“revert to wild type”), or enhance (“make worse”) the mutant phenotype. The goal is to identify the exact gene required for this suppression or enhancement, using smaller deficiency mutant strains that delete only a few genes. Such mutant deficiencies represent candidate NiPP1 modifying genes. The candidate genes will be knocked out by RNAi one by one to definitively determine the genes required for PP1 function in cell-to-cell adhesion and collective migration. Because many Drosophilagenes have human homologs, these studies of PP1 have implications for collective cell migration in humans

Drosophila Condensin II subunit Chromosome-associated protein D3 regulates cell fate determination through non-cell-autonomous signaling

Citation: Klebanow, L. R., Peshel, E. C., Schuster, A. T., De, K., Sarvepalli, K., Lemieux, M. E., . . . Longworth, M. S. (2016). Drosophila Condensin II subunit Chromosome-associated protein D3 regulates cell fate determination through non-cell-autonomous signaling. Development, 143(15), 2791-2802. doi:10.1242/dev.133686The pattern of the Drosophila melanogaster adult wing is heavily influenced by the expression of proteins that dictate cell fate decisions between intervein and vein during development. dSRF (Blistered) expression in specific regions of the larval wing disc promotes intervein cell fate, whereas EGFR activity promotes vein cell fate. Here, we report that the chromatin-organizing protein CAP-D3 acts to dampen dSRF levels at the anterior/posterior boundary in the larval wing disc, promoting differentiation of cells into the anterior crossvein. CAP-D3 represses KNOT expression in cells immediately adjacent to the anterior/posterior boundary, thus blocking KNOT-mediated repression of EGFR activity and preventing cell death. Maintenance of EGFR activity in these cells depresses dSRF levels in the neighboring anterior crossvein progenitor cells, allowing them to differentiate into vein cells. These findings uncover a novel transcriptional regulatory network influencing Drosophila wing vein development, and are the first to identify a Condensin II subunit as an important regulator of EGFR activity and cell fate determination in vivo

Beyond the Red, Purple, and Blue: Election Law Issues in 2012

The Symposium Welcome was given by Clint A. Nichols, the Allen Chair Editor for the University of Richmond Law Review, and Wendy C. Perdue, Dean & Professor of Law at the University of Richmond School of Law. The “Get out the vote?” session was presented by Keesha M. Gaskins, Senior Counsel with the Brennan Center for Justice at New York University; Steven F. Huefner, Professor of Law and Director of Clinical Programs at The Ohio State University Moritz College of Law; Joshua N. Lief, Senior Assistant Attorney General for the Commonwealth of Virginia; and Michael J. Pitts, Professor of Law and Dean’s Fellow at Indiana University’s Robert H. McKinney School of Law. The “Third Parties to the Process” session was presented by Jocelyn F. Benson, Associate Professor of Law at Wayne State University Law School; Joshua A. Douglas, Assistant Professor of Law at the University of Kentucky College of Law; and Rebecca Green, Professor of the Practice of Law and Co-Director of the Election Law Program at the William & Mary Law School. The “Drawing the Lines” session was presented by Keesha M. Gaskins, Senior Counsel with the Brennan Center for Justice at New York University; Dale Ho, Assistant Counsel with the NAACP Legal Defense and Educational Fund; Dr. Michael P. McDonald, Associate Professor of Government and Politics at George Mason University; Donald Palmer, Secretary of the Virginia State Board of Elections; and Rob Richie, Executive Director of FairVote

A case study of physical and social barriers to hygiene and child growth in remote Australian Aboriginal communities

Background\ud Despite Australia's wealth, poor growth is common among Aboriginal children living in remote communities. An important underlying factor for poor growth is the unhygienic state of the living environment in these communities. This study explores the physical and social barriers to achieving safe levels of hygiene for these children.\ud \ud Methods\ud A mixed qualitative and quantitative approach included a community level cross-sectional housing infrastructure survey, focus groups, case studies and key informant interviews in one community.\ud \ud Results\ud We found that a combination of crowding, non-functioning essential housing infrastructure and poor standards of personal and domestic hygiene underlie the high burden of infection experienced by children in this remote community.\ud \ud Conclusion\ud There is a need to address policy and the management of infrastructure, as well as key parenting and childcare practices that allow the high burden of infection among children to persist. The common characteristics of many remote Aboriginal communities in Australia suggest that these findings may be more widely applicable

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome After SARS-CoV-2 Infection

IMPORTANCE: Chronic symptoms reported following an infection with SARS-CoV-2, such as cognitive problems, overlap with symptoms included in the definition of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). OBJECTIVE: To evaluate the prevalence of ME/CFS-like illness subsequent to acute SARS-CoV-2 infection, changes in ME/CFS symptoms through 12 months of follow-up, and the association of ME/CFS symptoms with SARS-CoV-2 test results at the acute infection-like index illness. DESIGN, SETTING, AND PARTICIPANTS: This prospective, multisite, longitudinal cohort study (Innovative Support for Patients with SARS-CoV-2 Infections Registry [INSPIRE]) enrolled participants from December 11, 2020, to August 29, 2022. Participants were adults aged 18 to 64 years with acute symptoms suggestive of SARS-CoV-2 infection who received a US Food and Drug Administration-approved SARS-CoV-2 test at the time of illness and did not die or withdraw from the study by 3 months. Follow-up surveys were collected through February 28, 2023. EXPOSURE: COVID-19 status (positive vs negative) at enrollment. MAIN OUTCOME AND MEASURES: The main outcome was the weighted proportion of participants with ME/CFS-like illness based on the 2015 Institute of Medicine clinical case definition using self-reported symptoms. RESULTS: A total of 4378 participants were included in the study. Most were female (3226 [68.1%]). Mean (SD) age was 37.8 (11.8) years. The survey completion rates ranged from 38.7% (3613 of 4738 participants) to 76.3% (1835 of 4738) and decreased over time. The weighted proportion of participants identified with ME/CFS-like illness did not change significantly at 3 through 12 months of follow-up and was similar in the COVID-19-positive (range, 2.8%-3.7%) and COVID-19-negative (range, 3.1%-4.5%) groups. Adjusted analyses revealed no significant difference in the odds of ME/CFS-like illness at any time point between COVID-19-positive and COVID-19-negative individuals (marginal odds ratio range, 0.84 [95% CI, 0.42-1.67] to 1.18 [95% CI, 0.55-2.51]). CONCLUSIONS AND RELEVANCE: In this prospective cohort study, there was no evidence that the proportion of participants with ME/CFS-like illness differed between those infected with SARS-CoV-2 vs those without SARS-CoV-2 infection up to 12 months after infection. A 3% to 4% prevalence of ME/CFS-like illness after an acute infection-like index illness would impose a high societal burden given the millions of persons infected with SARS-CoV-2

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Dynamic Myosin Activation Promotes Collective Morphology And Migration By Locally Balancing Oppositional Forces From Surrounding Tissue

Migrating cells need to overcome physical constraints from the local microenvironment to navigate their way through tissues. Cells that move collectively have the additional challenge of negotiating complex environments in vivo while maintaining cohesion of the group as a whole. The mechanisms by which collectives maintain a migratory morphology while resisting physical constraints from the surrounding tissue are poorly understood. Drosophila border cells represent a genetic model of collective migration within a cell-dense tissue. Border cells move as a cohesive group of 6-10 cells, traversing a network of large germ line-derived nurse cells within the ovary. Here we show that the border cell cluster is compact and round throughout their entire migration, a shape that is maintained despite the mechanical pressure imposed by the surrounding nurse cells. Nonmuscle myosin II (Myo-II) activity at the cluster periphery becomes elevated in response to increased constriction by nurse cells. Furthermore, the distinctive border cell collective morphology requires highly dynamic and localized enrichment of Myo-II. Thus, activated Myo-II promotes cortical tension at the outer edge of the migrating border cell cluster to resist compressive forces from nurse cells. We propose that dynamic actomyosin tension at the periphery of collectives facilitates their movement through restrictive tissues