Papers by Benjamin Podbilewicz
Wiley-VCH Verlag GmbH & Co. KGaA eBooks, Mar 27, 2006
Journal of Cell Biology, Apr 1, 2019
Cell-cell fusion remains the least understood type of membrane fusion process. However, the last ... more Cell-cell fusion remains the least understood type of membrane fusion process. However, the last few years have brought about major advances in understanding fusion between gametes, myoblasts, macrophages, trophoblasts, epithelial, cancer, and other cells in normal development and in diseases. While different cell fusion processes appear to proceed via similar membrane rearrangements, proteins that have been identified as necessary and sufficient for cell fusion (fusogens) use diverse mechanisms. Some fusions are controlled by a single fusogen; other fusions depend on several proteins that either work together throughout the fusion pathway or drive distinct stages. Furthermore, some fusions require fusogens to be present on both fusing membranes, and in other fusions, fusogens have to be on only one of the membranes. Remarkably, some of the proteins that fuse cells also sculpt single cells, repair neurons, promote scission of endocytic vesicles, and seal phagosomes. In this review, we discuss the properties and diversity of the known proteins mediating cell-cell fusion and highlight their different working mechanisms in various contexts.
Seminars in Cell & Developmental Biology, Dec 1, 2016
SummaryMammalian sperm-egg adhesion depends on the trans-interaction between the sperm-specific t... more SummaryMammalian sperm-egg adhesion depends on the trans-interaction between the sperm-specific type I glycoprotein IZUMO1 and its oocyte-specific GPI-anchored receptor JUNO. However, the mechanisms and proteins (fusogens) which mediate the following step of gamete fusion remain unknown. Using live imaging and content mixing assays in a heterologous system and structure-guided mutagenesis, we unveil an unexpected function for IZUMO1 in cell-to-cell fusion. We show that IZUMO1 alone is sufficient to induce fusion, and that this ability is retained in a mutant unable to bind JUNO. On the other hand, a triple mutation in exposed aromatic residues prevents this fusogenic activity without impairing JUNO interaction. Our findings suggest a second, crucial function for IZUMO1 as a unilateral mouse gamete fusogen.HighlightsIZUMO1 expression in somatic cells in culture induces cell-to-cell fusionThe fusogenic activity of IZUMO1 is unilateralCell fusion is independent of the binding of IZUMO1...
Frontiers in Cell and Developmental Biology, 2022
Gamete fusion is the climax of fertilization in all sexually reproductive organisms, from unicell... more Gamete fusion is the climax of fertilization in all sexually reproductive organisms, from unicellular fungi to humans. Similarly to other cell-cell fusion events, gamete fusion is mediated by specialized proteins, named fusogens, that overcome the energetic barriers during this process. In recent years, HAPLESS 2/GENERATIVE CELL-SPECIFIC 1 (HAP2/GCS1) was identified as the fusogen mediating sperm-egg fusion in flowering plants and protists, being both essential and sufficient for the membrane merger in some species. The identification of HAP2/GCS1 in invertebrates, opens the possibility that a similar fusogen may be used in vertebrate fertilization. HAP2/GCS1 proteins share a similar structure with two distinct families of exoplasmic fusogens: the somatic Fusion Family (FF) proteins discovered in nematodes, and class II viral glycoproteins (e.g., rubella and dengue viruses). Altogether, these fusogens form the Fusexin superfamily. While some attributes are shared among fusexins, for...
bioRxiv (Cold Spring Harbor Laboratory), Jul 7, 2016
The convoluted architecture of dendritic arbors poses a challenge to understanding agedependent a... more The convoluted architecture of dendritic arbors poses a challenge to understanding agedependent alterations and regeneration following injury. Here, we show that induction of cellular fusogens can remodel and facilitate regeneration of dendrites in polymodal PVD neurons of aging Caenorhabditis elegans. Using whole-animal live imaging, we find that the PVD dendritic trees, composed of repetitive "menorah" units, show age-dependent hyperbranching, disorganization, and loss of self-avoidance. These processes, while independent of canonical lifespan-regulating pathways, can be partially rescued by ectopic expression of the fusogen EFF-1. Furthermore, the decreased capacity of old animals to repair laser-induced severed dendrites via auto-fusion can be restored by reducing DAF-2 (Insulin/IGF-1Receptor) function or by ectopic expression of the EFF-1 paralog AFF-1. Our findings demonstrate that fusogens are sufficient to maintain the dendritic arbor structure and increase its regeneration potential in aging animals. These antiaging strategies can be potentially applied to other organisms to protect them from neurodegeneration.
Current Biology, Nov 20, 2007
Background: A surprising amount of developmental variation has been observed for otherwise highly... more Background: A surprising amount of developmental variation has been observed for otherwise highly conserved features, a phenomenon known as developmental system drift. Either stochastic processes (e.g., drift and absence of selection-independent constraints) or deterministic processes (e.g., selection or constraints) could be the predominate mechanism for the evolution of such variation. We tested whether evolutionary patterns of change were unbiased or biased, as predicted by the stochastic or deterministic hypotheses, respectively. As a model, we used the nematode vulva, a highly conserved, essential organ, the development of which has been intensively studied in the model systems Caenorhabditis elegans and Pristionchus pacificus. Results: For 51 rhabditid species, we analyzed more than 40 characteristics of vulva development, including cell fates, fate induction, cell competence, division patterns, morphogenesis, and related aspects of gonad development. We then defined individual characters and plotted their evolution on a phylogeny inferred for 65 species from three nuclear gene sequences. This taxon-dense phylogeny provides for the first time a highly resolved picture of rhabditid evolution and allows the reconstruction of the number and directionality of changes in the vulva development characters. We found an astonishing amount of variation and an even larger number of evolutionary changes, suggesting a high degree of homoplasy (convergences and reversals). Surprisingly, only two characters showed unbiased evolution. Evolution of all other characters was biased.
Genes Development, 2002
General mechanisms by which Hox genes establish cell fates are known. However, a few Hox effector... more General mechanisms by which Hox genes establish cell fates are known. However, a few Hox effectors mediating cell behaviors have been identified. Here we found the first effector of LIN-39/HoxD4/Dfd in Caenorhabditis elegans.
The Embo Journal, Dec 1, 1990
We have developed an in vitro system for studying membrane transport during receptor-mediated end... more We have developed an in vitro system for studying membrane transport during receptor-mediated endocytosis. Using nitrocellulose disruption to permeabilize selectively the apical domain of ifiter-grown MIDCK cells, the recycling of receptor-bound transferrin (Tfn) from an intracellular pool was reconstituted in vitro with a rate and efficiency similar to that of intact cells. Tfn and Tfn receptor recycling from endosomes back to the cell surface was dependent on added ATP and cytosol-derived proteins. Thus, incubation of intact cells under conditions of ATP depletion resulted in the clearance of Tfn receptors from the basolateral membrane, this was reversible upon removal of the energy poisons. Reappearance of previously intemalized receptors could also be obtained in disrupted cells but required the addition of both ATP and cytosol to the assay mixture. Similarly, when intact cells were allowed to internalize labeled Tfn prior to disruption, efficient and rapid release of ligand back into the medium was markedly stimulated by ATP and cytosol. Recycling was judged to be both selective and vectorial since only the expected small fraction of a previously internalized horseradish peroxidase was released after addition of ATP and cytosol, and release was primarily into the basal medium. While the cytosol contributed one or more protein factors, none was sensitive to N-ethyhnaleimide. Alkylation of the disrupted cells, however, did inactivate recycling.
F1000 - Post-publication peer review of the biomedical literature, 2000
F1000 - Post-publication peer review of the biomedical literature, 2000
Methods in Molecular Biology™, 2008
In the nematode Caenorhabditis elegans, 300 of the 959 somatic nuclei present in the adult hermap... more In the nematode Caenorhabditis elegans, 300 of the 959 somatic nuclei present in the adult hermaphrodite are located in syncytia. These syncytia are formed by the fusion of mononucleate cells throughout embryonic and postembryonic development. These cell fusions occur in a well-characterized stereotypical pattern, allowing investigators to study many cell fusion events at the molecular and cellular levels. Using tools that allow visualization of cell membranes, cell junctions, and cell cytoplasm during fusion, genetic screens have identified many C. elegans cell fusion genes, including those that regulate the fusion cell fate decision and two genes that encode components of the cell fusion machinery.
Genes & Development, 2002
General mechanisms by which Hox genes establish cell fates are known. However, a few Hox effector... more General mechanisms by which Hox genes establish cell fates are known. However, a few Hox effectors mediating cell behaviors have been identified. Here we found the first effector of LIN-39/HoxD4/Dfd in Caenorhabditis elegans.
Developmental Dynamics, 2000
Cell fusion is a universal process that occurs during fertilization and in the formation of organ... more Cell fusion is a universal process that occurs during fertilization and in the formation of organs such as muscles, placenta, and bones. Very little is known about the molecular and cellular mechanisms of cell fusion during pattern formation. Here we review the dynamic anatomy of all cell fusions during embryonic and postembryonic development in an organism. Nearly all the cell fates and cell lineages are invariant in the nematode C. elegans and one third of the cells that are born fuse to form 44 syncytia in a reproducible and stereotyped way. To explain the function of cell fusion in organ formation we propose the fusomorphogenetic model as a simple cellular mechanism to efficiently redistribute membranes using a combination of cell fusion and polarized membrane recycling during morphogenesis. Thus, regulated intercellular and intracellular membrane fusion processes may drive elongation of the embryo as well as postembryonic organ formation in C. elegans. Finally, we use the fusomorphogenetic hypothesis to explain the role of cell fusion in the formation of organs like muscles, bones, and placenta in mammals and other species and to speculate on how the intracellular machinery that drive fusomorphogenesis may have evolved. Dev Dyn 2000;218:30 -51.
Developmental Biology, 2000
posterior halves develop autonomously. Contrary to prevailing hypotheses which proposed three cel... more posterior halves develop autonomously. Contrary to prevailing hypotheses which proposed three cell fates (1°, 2°, and 3°), we found that each of the seven rings is a product of a discrete structural pathway that is derived from arrays of seven distinct cell fates (A, B, C, D, E, F, and H). We have also shown how autonomous ring formation is the morphogenetic force that drives invagination of the vulva.
Current Biology, 2007
Background: A surprising amount of developmental variation has been observed for otherwise highly... more Background: A surprising amount of developmental variation has been observed for otherwise highly conserved features, a phenomenon known as developmental system drift. Either stochastic processes (e.g., drift and absence of selection-independent constraints) or deterministic processes (e.g., selection or constraints) could be the predominate mechanism for the evolution of such variation. We tested whether evolutionary patterns of change were unbiased or biased, as predicted by the stochastic or deterministic hypotheses, respectively. As a model, we used the nematode vulva, a highly conserved, essential organ, the development of which has been intensively studied in the model systems Caenorhabditis elegans and Pristionchus pacificus. Results: For 51 rhabditid species, we analyzed more than 40 characteristics of vulva development, including cell fates, fate induction, cell competence, division patterns, morphogenesis, and related aspects of gonad development. We then defined individual characters and plotted their evolution on a phylogeny inferred for 65 species from three nuclear gene sequences. This taxon-dense phylogeny provides for the first time a highly resolved picture of rhabditid evolution and allows the reconstruction of the number and directionality of changes in the vulva development characters. We found an astonishing amount of variation and an even larger number of evolutionary changes, suggesting a high degree of homoplasy (convergences and reversals). Surprisingly, only two characters showed unbiased evolution. Evolution of all other characters was biased.
BioEssays, 2003
The ability of two or more cells to unite to form a new syncytial cell has been utilized in metaz... more The ability of two or more cells to unite to form a new syncytial cell has been utilized in metazoans throughout evolution to form many complex organs, such as muscles, bones and placentae. This requires migration, recognition and adhesion between cells together with fusion of their plasma membranes and rearrangement of their cytoplasmic contents. Until recently, understanding of the mechanisms of cell fusion was restricted to fusion between enveloped viruses and their target cells. The identification of new factors that take part in developmental cell fusion in C. elegans opens the way to understanding how cells fuse and what the functions of this process are. In this review, we describe current knowledge on the mechanisms and putative roles of developmental cell fusion in C. elegans and how cell fusion is regulated, together with other intercellular processes to promote organogenesis.
Development (Cambridge, England), 2017
The aging brain undergoes structural changes that affect brain homeostasis, neuronal function and... more The aging brain undergoes structural changes that affect brain homeostasis, neuronal function and consequently cognition. The complex architecture of dendritic arbors poses a challenge to understanding age-dependent morphological alterations, behavioral plasticity and remodeling following brain injury. Here, we use the PVD polymodal neurons of C. elegans as a model to study how aging affects neuronal plasticity. Using confocal live imaging of C. elegans PVD neurons, we demonstrate age-related progressive morphological alterations of intricate dendritic arbors. We show that mutations in daf-2, which encodes an insulin-like growth factor receptor ortholog, fail to inhibit the progressive morphological aging of dendrites and do not prevent the minor decline in response to harsh touch during aging. We uncovered that PVD aging is characterized by a major decline in the regenerative potential of dendrites following experimental laser dendrotomy. Furthermore, the remodeling of transected d...
Organogenetic Gene Networks, 2016
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Papers by Benjamin Podbilewicz