Collective cell migration of Dictyostelium without cAMP oscillations at multicellular stages.
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ABSTRACT:
SUBMITTER: Hashimura H
PROVIDER: S-EPMC6345914 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:MFSD8 is a transmembrane protein that has been reported to transport chloride ions across the lysosomal membrane. Mutations in MFSD8 are associated with a subtype of Batten disease called CLN7 disease. Batten disease encompasses a family of 13 inherited neurodegenerative lysosomal storage diseases collectively referred to as the neuronal ceroid lipofuscinoses (NCLs). Previous work identified an ortholog of human MFSD8 in the social amoeba D. discoideum (gene: mfsd8, protein: Mfsd8), reported its localization to endocytic compartments, and demonstrated its involvement in protein secretion. In this study, we further characterized the effects of mfsd8 loss during D. discoideum growth and early stages of multicellular development. During growth, mfsd8 - cells displayed increased rates of proliferation, pinocytosis, and expansion on bacterial lawns. Loss of mfsd8 also increased cell size, inhibited cytokinesis, affected the intracellular and extracellular levels of the quorum-sensing protein autocrine proliferation repressor A, and altered lysosomal enzyme activity. During the early stages of development, loss of mfsd8 delayed aggregation, which we determined was at least partly due to impaired cell-substrate adhesion, defects in protein secretion, and alterations in lysosomal enzyme activity. Overall, these results show that Mfsd8 plays an important role in modulating a variety of processes during the growth and early development of D. discoideum.
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Project description:Epithelial sheet spreading is a fundamental cellular process that must be coordinated with cell division and differentiation to restore tissue integrity. Here we use consecutive serum deprivation and re-stimulation to reconstruct biphasic collective migration and proliferation in cultured sheets of human keratinocytes. In this system, a burst of long-range coordinated locomotion is rapidly generated throughout the cell sheet in the absence of wound edges. Migrating cohorts reach correlation lengths of several millimeters and display dependencies on epidermal growth factor receptor-mediated signaling, self-propelled polarized migration, and a G1/G0 cell cycle environment. The migration phase is temporally and spatially aligned with polarized cell divisions characterized by pre-mitotic nuclear migration to the cell front and asymmetric partitioning of nuclear promyelocytic leukemia bodies and lysosomes to opposite daughter cells. This study investigates underlying mechanisms contributing to the stark contrast between cells in a static quiescent state compared to the long-range coordinated collective migration seen in contact with blood serum.
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Project description:Collective cell migration in response to a chemical cue occurs in many biological processes such as morphogenesis and cancer metastasis. Clusters of migratory cells in these systems are capable of responding to gradients of <1% difference in chemical concentration across a cell length. Multicellular systems are extremely sensitive to their environment, and although the limits to multicellular sensing are becoming known, how this information leads to coherent migration remains poorly understood. We develop a computational model of multicellular sensing and migration in which groups of cells collectively measure noisy chemical gradients. The output of the sensing process is coupled to the polarization of individual cells to model migratory behavior. Through the use of numerical simulations, we find that larger clusters of cells detect the gradient direction with higher precision and thus achieve stronger polarization bias, but larger clusters also induce more drag on collective motion. The trade-off between these two effects leads to an optimal cluster size for most efficient migration. We discuss how our model could be validated using simple, phenomenological experiments.
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Project description:Coordination of neurite morphogenesis with surrounding tissues is crucial to the establishment of neural circuits, but the underlying cellular and molecular mechanisms remain poorly understood. We show that neurons in a C. elegans sensory organ, called the amphid, undergo a collective dendrite extension to form the sensory nerve. The amphid neurons first assemble into a multicellular rosette. The vertex of the rosette, which becomes the dendrite tips, is attached to the anteriorly migrating epidermis and carried to the sensory depression, extruding the dendrites away from the neuronal cell bodies. Multiple adhesion molecules including DYF-7, SAX-7, HMR-1 and DLG-1 function redundantly in rosette-to-epidermis attachment. PAR-6 is localized to the rosette vertex and dendrite tips, and promotes DYF-7 localization and dendrite extension. Our results suggest a collective mechanism of neurite extension that is distinct from the classical pioneer-follower model and highlight the role of mechanical cues from surrounding tissues in shaping neurites.
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Project description:BackgroundThe cell cycle of all organisms includes mass increase by a factor of two, replication of the genetic material, segregation of the genome to different parts of the cell, and cell division into two daughter cells. It is tightly regulated and typically includes cell cycle-specific oscillations of the levels of transcripts, proteins, protein modifications, and signaling molecules. Until now cell cycle-specific transcriptome changes have been described for four eukaryotic species ranging from yeast to human, but only for two prokaryotic species. Similarly, oscillations of small signaling molecules have been identified in very few eukaryotic species, but not in any prokaryote.ResultsA synchronization procedure for the archaeon Halobacterium salinarum was optimized, so that nearly 100% of all cells divide in a time interval that is 1/4th of the generation time of exponentially growing cells. The method was used to characterize cell cycle-dependent transcriptome changes using a genome-wide DNA microarray. The transcript levels of 87 genes were found to be cell cycle-regulated, corresponding to 3% of all genes. They could be clustered into seven groups with different transcript level profiles. Cluster-specific sequence motifs were detected around the start of the genes that are predicted to be involved in cell cycle-specific transcriptional regulation. Notably, many cell cycle genes that have oscillating transcript levels in eukaryotes are not regulated on the transcriptional level in H. salinarum. Synchronized cultures were also used to identify putative small signaling molecules. H. salinarum was found to contain a basal cAMP concentration of 200 microM, considerably higher than that of yeast. The cAMP concentration is shortly induced directly prior to and after cell division, and thus cAMP probably is an important signal for cell cycle progression.ConclusionThe analysis of cell cycle-specific transcriptome changes of H. salinarum allowed to identify a strategy of transcript level regulation that is different from all previously characterized species. The transcript levels of only 3% of all genes are regulated, a fraction that is considerably lower than has been reported for four eukaryotic species (6%-28%) and for the bacterium C. crescentus (19%). It was shown that cAMP is present in significant concentrations in an archaeon, and the phylogenetic profile of the adenylate cyclase indicates that this signaling molecule is widely distributed in archaea. The occurrence of cell cycle-dependent oscillations of the cAMP concentration in an archaeon and in several eukaryotic species indicates that cAMP level changes might be a phylogenetically old signal for cell cycle progression.
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