Conserved chamber-specific polyploidy maintains heart function in Drosophila.

Developmentally programmed polyploidy (whole-genome duplication) of cardiomyocytes is common across evolution. Functions of such polyploidy are essentially unknown. Here, in both Drosophila larvae and human organ donors, we reveal distinct polyploidy levels in cardiac organ chambers. In Drosophila, differential growth and cell cycle signal sensitivity leads the heart chamber to reach a higher ploidy/cell size relative to the aorta chamber. Cardiac ploidy-reduced animals exhibit reduced heart chamber size, stroke volume and cardiac output, and acceleration of circulating hemocytes. These Drosophila phenotypes mimic human cardiomyopathies. Our results identify productive and likely conserved roles for polyploidy in cardiac chambers and suggest that precise ploidy levels sculpt many developing tissues. These findings of productive cardiomyocyte polyploidy impact efforts to block developmental polyploidy to improve heart injury recovery.

Conserved Chamber-Specific Polyploidy Maintains Heart Function in Drosophila.

Developmentally programmed polyploidy (whole-genome-duplication) of cardiomyocytes is common across evolution. Functions of such polyploidy are essentially unknown. Here, we reveal roles for precise polyploidy levels in cardiac tissue. We highlight a conserved asymmetry in polyploidy level between cardiac chambers in Drosophila larvae and humans. In Drosophila , differential Insulin Receptor (InR) sensitivity leads the heart chamber to reach a higher ploidy/cell size relative to the aorta chamber. Cardiac ploidy-reduced animals exhibit reduced heart chamber size, stroke volume, cardiac output, and acceleration of circulating hemocytes. These Drosophila phenotypes mimic systemic human heart failure. Using human donor hearts, we reveal asymmetry in nuclear volume (ploidy) and insulin signaling between the left ventricle and atrium. Our results identify productive and likely conserved roles for polyploidy in cardiac chambers and suggest precise ploidy levels sculpt many developing tissues. These findings of productive cardiomyocyte polyploidy impact efforts to block developmental polyploidy to improve heart injury recovery.

Communal living: the role of polyploidy and syncytia in tissue biology.

Multicellular organisms are composed of tissues with diverse cell sizes. Whether a tissue primarily consists of numerous, small cells as opposed to fewer, large cells can impact tissue development and function. The addition of nuclear genome copies within a common cytoplasm is a recurring strategy to manipulate cellular size within a tissue. Cells with more than two genomes can exist transiently, such as in developing germlines or embryos, or can be part of mature somatic tissues. Such nuclear collectives span multiple levels of organization, from mononuclear or binuclear polyploid cells to highly multinucleate structures known as syncytia. Here, we review the diversity of polyploid and syncytial tissues found throughout nature. We summarize current literature concerning tissue construction through syncytia and/or polyploidy and speculate why one or both strategies are advantageous.

Accelerated cell cycles enable organ regeneration under developmental time constraints in the Drosophila hindgut.

Individual organ development must be temporally coordinated with development of the rest of the organism. As a result, cell division cycles in a developing organ occur on a relatively fixed timescale. Despite this, many developing organs can regenerate cells lost to injury. How organs regenerate within the time constraints of organism development remains unclear. Here, we show that the developing Drosophila hindgut regenerates by accelerating the mitotic cell cycle. This process is achieved by decreasing G1 length and requires the JAK/STAT ligand unpaired-3. Mitotic capacity is then terminated by the steroid hormone ecdysone receptor and the Sox transcription factor Dichaete. These two factors converge on regulation of a hindgut-specific enhancer of fizzy-related, a negative regulator of mitotic cyclins. Our findings reveal how the cell-cycle machinery and cytokine signaling can be adapted to accomplish developmental organ regeneration.

Cytoplasmic sharing through apical membrane remodeling.

Multiple nuclei sharing a common cytoplasm are found in diverse tissues, organisms, and diseases. Yet, multinucleation remains a poorly understood biological property. Cytoplasm sharing invariably involves plasma membrane breaches. In contrast, we discovered cytoplasm sharing without membrane breaching in highly resorptive Drosophila rectal papillae. During a six-hour developmental window, 100 individual papillar cells assemble a multinucleate cytoplasm, allowing passage of proteins of at least 62 kDa throughout papillar tissue. Papillar cytoplasm sharing does not employ canonical mechanisms such as incomplete cytokinesis or muscle fusion pore regulators. Instead, sharing requires gap junction proteins (normally associated with transport of molecules < 1 kDa), which are positioned by membrane remodeling GTPases. Our work reveals a new role for apical membrane remodeling in converting a multicellular epithelium into a giant multinucleate cytoplasm.

Most cells are self-contained ­ they have a cell membrane that delimits and therefore defines the cell, separating it from other cells and from its environment. But sometimes several cells interconnect and form collectives so they can pool their internal resources. Some of the best-known examples of this happen in animal muscle cells and in the placenta of mammals. These cell collectives share their cytoplasm ­ the fluid within the cell membrane that contains the cell organelles ­ in one of two ways. Cells can either remain linked instead of breaking away when they divide, or they can fuse their membranes with those of their neighbors. Working out how cells link to their neighbors is difficult when so few examples of cytoplasm sharing are available for study. One way to tackle this is to try and find undiscovered cell collectives in an animal that is already heavily studied in the lab, such as the fruit fly Drosophila melanogaster. Peterson et al. used a genetic system that randomly labels each cell of the developing fly with one of three fluorescent proteins. These proteins are big and should not move between cells unless they are sharing their cytoplasm. This means that any cell containing two or more different colors of fluorescent protein must be connected to at least one of its neighbors. The experiment revealed that the cells of the fruit fly rectum share their cytoplasm in a way never seen before. This sharing occurs at a consistent point in the development of the fruit fly and uses a different set of genes to those used by interconnecting cells in mammal muscles and placenta. These genes produce proteins that reshape the membranes of the cells and fit them with gap junctions ­ tiny pores that cross from one membrane to the next, allowing the passage of very small molecules. In this case, the gap junctions allowed the cells to share molecules much larger than seen before. The result is a giant cell membrane containing the cytoplasm and organelles of more than a hundred individual cells. These findings expand scientists' understanding of how cells in a tissue can share cytoplasm and resources. They also introduce a new tissue in the fruit fly that can be used in future studies of cytoplasm sharing. Relatives of fruit flies, including fruit pests and mosquitos, have similar cell structure to the fruit fly, which means that further investigations using this system could result in advances in agriculture or human health.

Physiology, Development, and Disease Modeling in the Drosophila Excretory System.

The insect excretory system contains two organ systems acting in concert: the Malpighian tubules and the hindgut perform essential roles in excretion and ionic and osmotic homeostasis. For over 350 years, these two organs have fascinated biologists as a model of organ structure and function. As part of a recent surge in interest, research on the Malpighian tubules and hindgut of Drosophila have uncovered important paradigms of organ physiology and development. Further, many human disease processes can be modeled in these organs. Here, focusing on discoveries in the past 10 years, we provide an overview of the anatomy and physiology of the Drosophila excretory system. We describe the major developmental events that build these organs during embryogenesis, remodel them during metamorphosis, and repair them following injury. Finally, we highlight the use of the Malpighian tubules and hindgut as accessible models of human disease biology. The Malpighian tubule is a particularly excellent model to study rapid fluid transport, neuroendocrine control of renal function, and modeling of numerous human renal conditions such as kidney stones, while the hindgut provides an outstanding model for processes such as the role of cell chirality in development, nonstem cell-based injury repair, cancer-promoting processes, and communication between the intestine and nervous system.