scholarly journals Transcriptional control of apical protein clustering drives de novo cell polarity establishment in the early mouse embryo

2020 ◽  
Author(s):  
Meng Zhu ◽  
Peizhe Wang ◽  
Charlotte E. Handford ◽  
Jie Na ◽  
Magdalena Zernicka-Goetz
Keyword(s):  
Cell Polarity ◽  
Mouse Embryo ◽  
Transcriptional Control ◽  
Molecular Mechanisms ◽  
Rho Gtpase ◽  
De Novo ◽  
Cell Polarization ◽  
Mammalian Embryo ◽  
Lineage Differentiation ◽  
Polarity Establishment

SummaryThe establishment of cell polarity de novo in the early mammalian embryo triggers the transition from totipotency to differentiation to generate embryonic and extra-embryonic lineages. However, the molecular mechanisms governing the timing of cell polarity establishment remain unknown. Here, we identify stage-dependent transcription of Tfap2c and Tead4 as well as Rho GTPase signaling as key for the onset of cell polarization. Importantly, advancing their activity can induce precocious cell polarization and ectopic lineage differentiation in a cell-autonomous manner. Moreover, we show that the asymmetric clustering of apical proteins, regulated by Tfap2c-Tead4, and not actomyosin flow, mediates apical protein polarization. These findings identify the long-sought mechanism for the onset of polarization and the first lineage segregation in the mouse embryo.

scholarly journals Interaction between a Ras and a Rho GTPase Couples Selection of a Growth Site to the Development of Cell Polarity in Yeast

2003 ◽  
Vol 14 (12) ◽  
pp. 4958-4970 ◽  
Author(s):  
Keith G. Kozminski ◽  
Laure Beven ◽  
Elizabeth Angerman ◽  
Amy Hin Yan Tong ◽  
Charles Boone ◽  
...  
Keyword(s):  
Cell Polarity ◽  
Rho Gtpase ◽  
Cell Cortex ◽  
Nucleotide Exchange ◽  
Yeast Saccharomyces Cerevisiae ◽  
Growth Site ◽  
Ras Family ◽  
Rho Family ◽  
Polarity Establishment ◽  
Selection Of

Polarized cell growth requires the coupling of a defined spatial site on the cell cortex to the apparatus that directs the establishment of cell polarity. In the budding yeast Saccharomyces cerevisiae, the Ras-family GTPase Rsr1p/Bud1p and its regulators select the proper site for bud emergence on the cell cortex. The Rho-family GTPase Cdc42p and its associated proteins then establish an axis of polarized growth by triggering an asymmetric organization of the actin cytoskeleton and secretory apparatus at the selected bud site. We explored whether a direct linkage exists between the Rsr1p/Bud1p and Cdc42p GTPases. Here we show specific genetic interactions between RSR1/BUD1 and particular cdc42 mutants defective in polarity establishment. We also show that Cdc42p coimmunoprecipitated with Rsr1p/Bud1p from yeast extracts. In vitro studies indicated a direct interaction between Rsr1p/Bud1p and Cdc42p, which was enhanced by Cdc24p, a guanine nucleotide exchange factor for Cdc42p. Our findings suggest that Cdc42p interacts directly with Rsr1p/Bud1p in vivo, providing a novel mechanism by which direct contact between a Ras-family GTPase and a Rho-family GTPase links the selection of a growth site to polarity establishment.

scholarly journals aPKC: the Kinase that Phosphorylates Cell Polarity

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 903 ◽  
Author(s):  
Yang Hong
Keyword(s):  
Subcellular Localization ◽  
Cell Polarity ◽  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Cell Polarization ◽  
Kinase C ◽  
Dividing Cells ◽  
Cell Embryo ◽  
Powerful Mechanism ◽  
Anterior Posterior

Establishing and maintaining cell polarity are dynamic processes that necessitate complicated but highly regulated protein interactions. Phosphorylation is a powerful mechanism for cells to control the function and subcellular localization of a target protein, and multiple kinases have played critical roles in cell polarity. Among them, atypical protein kinase C (aPKC) is likely the most studied kinase in cell polarity and has the largest number of downstream substrates characterized so far. More than half of the polarity proteins that are essential for regulating cell polarity have been identified as aPKC substrates. This review covers mainly studies of aPKC in regulating anterior-posterior polarity in the worm one-cell embryo and apical-basal polarity in epithelial cells and asymmetrically dividing cells (for example, Drosophila neuroblasts). We will go through aPKC target proteins in cell polarity and discuss various mechanisms by which aPKC phosphorylation controls their subcellular localizations and biological functions. We will also review the recent progress in determining the detailed molecular mechanisms in spatial and temporal control of aPKC subcellular localization and kinase activity during cell polarization.

scholarly journals Epigenetic Modification Affecting Expression of Cell Polarity and Cell Fate Genes to Regulate Lineage Specification in the Early Mouse Embryo

2010 ◽  
Vol 21 (15) ◽  
pp. 2649-2660 ◽  
Author(s):  
David-Emlyn Parfitt ◽  
Magdalena Zernicka-Goetz
Keyword(s):  
Cell Fate ◽  
Cell Polarity ◽  
Mouse Embryo ◽  
Inner Cell Mass ◽  
Epigenetic Modification ◽  
Cell Mass ◽  
Time Lapse ◽  
Cell Polarization ◽  
Asymmetric Divisions

Formation of inner and outer cells of the mouse embryo distinguishes pluripotent inner cell mass (ICM) from differentiating trophectoderm (TE). Carm1, which methylates histone H3R17 and R26, directs cells to ICM rather that TE. To understand the mechanism by which this epigenetic modification directs cell fate, we generated embryos with in vivo–labeled cells of different Carm1 levels, using time-lapse imaging to reveal dynamics of their behavior, and related this to cell polarization. This shows that Carm1 affects cell fate by promoting asymmetric divisions, that direct one daughter cell inside, and cell engulfment, where neighboring cells with lower Carm1 levels compete for outside positions. This is associated with changes to the expression pattern and spatial distribution of cell polarity proteins: Cells with higher Carm1 levels show reduced expression and apical localization of Par3 and a dramatic increase in expression of PKCII, antagonist of the apical protein aPKC. Expression and basolateral localization of the mouse Par1 homologue, EMK1, increases concomitantly. Increased Carm1 also reduces Cdx2 expression, a transcription factor key for TE differentiation. These results demonstrate how the extent of a specific epigenetic modification could affect expression of cell polarity and fate-determining genes to ensure lineage allocation in the mouse embryo.

Cell motility: can Rho GTPases and microtubules point the way?

2001 ◽  
Vol 114 (21) ◽  
pp. 3795-3803 ◽  
Author(s):  
Torsten Wittmann ◽  
Clare M. Waterman-Storer
Keyword(s):  
Actin Cytoskeleton ◽  
Cell Motility ◽  
Rho Gtpases ◽  
Molecular Mechanisms ◽  
Rho Gtpase ◽  
Cell Types ◽  
Small Gtpases ◽  
Cell Polarization ◽  
Microtubule Cytoskeleton ◽  
Filament Bundles

Migrating cells display a characteristic polarization of the actin cytoskeleton. Actin filaments polymerise in the protruding front of the cell whereas actin filament bundles contract in the cell body, which results in retraction of the cell’s rear. The dynamic organization of the actin cytoskeleton provides the force for cell motility and is regulated by small GTPases of the Rho family, in particular Rac1, RhoA and Cdc42. Although the microtubule cytoskeleton is also polarized in a migrating cell, and microtubules are essential for the directed migration of many cell types, their role in cell motility is not well understood at a molecular level. Here, we discuss the potential molecular mechanisms for interplay of microtubules, actin and Rho GTPase signalling in cell polarization and motility. Recent evidence suggests that microtubules locally modulate the activity of Rho GTPases and, conversely, Rho GTPases might be responsible for the initial polarization of the microtubule cytoskeleton. Thus, microtubules might be part of a positive feedback mechanism that maintains the stable polarization of a directionally migrating cell.

Auxin-induced nanoclustering of membrane signaling complexes underlies cell polarity establishment in Arabidopsis

2019 ◽  
Author(s):  
Xue Pan ◽  
Linjing Fang ◽  
Jianfeng Liu ◽  
Betul Senay-Aras ◽  
Wenwei Lin ◽  
...  
Keyword(s):  
Cell Surface ◽  
Cell Polarity ◽  
Feedback Loop ◽  
Cortical Microtubule ◽  
Cell Polarization ◽  
Feedback Stabilization ◽  
Cell Surface Receptor ◽  
List Type ◽  
Pavement Cells ◽  
Polarity Establishment

AbstractCell polarity is fundamental to the development of both eukaryotic and prokaryotic organisms, yet the mechanism of its establishment remains poorly understood. Here we show that signal-activated nanoclustering of membrane proteins and a cytoskeleton-based feedback loop provide an important mechanism for the establishment of cell polarity. The phytohormone auxin promoted sterol-dependent nanoclustering of cell surface transmembrane receptor-like kinase 1 (TMK1) to initiate cell polarity during the morphogenesis of Arabidopsis puzzle piece-shaped leaf pavement cells (PC). Auxin-triggered nanoclustering of TMK1 stabilized flotillin-associated ordered nanodomains, which were essential for auxin-mediated formation of ROP6 GTPase nanoclusters that act downstream TMK1 to promote cortical microtubule ordering. Mathematical modeling further demonstrated the essential role of this auxin-mediated stabilization of TMK1 and ROP6 nanoclusters, and predicted the additional requirement of ROP6-dependent cortical microtubules for further stabilization of TMK1-sterol nanodomains and the polarization of PC. This prediction was experimentally validated by genetic and biochemical data. Our studies reveal a new paradigm for polarity establishment: A diffusive signal triggers cell polarization by activating cell surface receptor-mediated lateral segregation of signaling components and a cytoskeleton-mediated positive feedback loop of nanodomain stabilization.HighlightsSterols are required for cell polarity in Arabidopsis leaf epidermal cellsAuxin promotes lipid ordering and polar distribution of ordered lipid nanodomains at the plasma membrane (PM)Auxin stabilizes sterol-dependent nanoclustering of transmembrane kinase (TMK1), a PM auxin signal transducerAuxin-induced TMK1 nanoclustering is required but insufficient for cell polarizationMicrotubule-based feedback stabilization of the auxin-induced TMK1 nanodomains can generate cell polarity

Rho-GTPase-regulated vesicle trafficking in plant cell polarity

2014 ◽  
Vol 42 (1) ◽  
pp. 212-218 ◽  
Author(s):  
Xu Chen ◽  
Jiří Friml
Keyword(s):  
Cell Polarity ◽  
Plant Cell ◽  
Rho Gtpase ◽  
Vesicle Trafficking ◽  
Large Family ◽  
Small Gtpases ◽  
Cell Polarization ◽  
Cellular Mechanisms ◽  
Pavement Cells ◽  
Cytoskeleton Organization

ROPs (Rho of plants) belong to a large family of plant-specific Rho-like small GTPases that function as essential molecular switches to control diverse cellular processes including cytoskeleton organization, cell polarization, cytokinesis, cell differentiation and vesicle trafficking. Although the machineries of vesicle trafficking and cell polarity in plants have been individually well addressed, how ROPs co-ordinate those processes is still largely unclear. Recent progress has been made towards an understanding of the co-ordination of ROP signalling and trafficking of PIN (PINFORMED) transporters for the plant hormone auxin in both root and leaf pavement cells. PIN transporters constantly shuttle between the endosomal compartments and the polar plasma membrane domains, therefore the modulation of PIN-dependent auxin transport between cells is a main developmental output of ROP-regulated vesicle trafficking. The present review focuses on these cellular mechanisms, especially the integration of ROP-based vesicle trafficking and plant cell polarity.

scholarly journals Turnover Regulation of the Rho GTPase Cdc42 by Heat Shock Protein Chaperones and the MAPK Pathway Scaffold Bem4

2021 ◽  
Author(s):  
Paul J Cullen ◽  
Beatriz Gonzalez
Keyword(s):  
Heat Shock ◽  
Cell Polarity ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Mapk Pathway ◽  
Cell Types ◽  
Cell Polarization ◽  
Extrinsic Cues ◽  
Dependent Cell ◽  
Map Kinase Pathway

All cells maintain an axis of polarity that directs the orientation of growth. Cell polarity can be reorganized during development and in response to extrinsic cues to produce new cell types. Rho GTPases are central regulators of cell polarity and signal-dependent cell differentiation. We show here that one of the best understood Rho GTPases, the highly conserved yeast Cdc42p, is turned over by members of the Heat Shock family of Proteins (HSPs). The Hsp40p chaperone, Ydj1p, was required for turnover of Cdc42p by the NEDD4 E3 ubiquitin ligase, Rsp5p, in the proteosome. Cdc42p turnover was regulated by HSPs at high temperatures, and in aging cells where the protein formed aggregates, implicating HSPs in Rho GTPase quality control. We also show that Cdc42pQ61L, which mimics the active (GTP-bound) conformation of the protein, was turned over at elevated levels by Ydj1p and Rsp5p. A turnover-defective version of Cdc42pQ61L led to multibudding phenotypes, implicating Cdc42 turnover in singularity in cell polarization. Cdc42p turnover also impacted MAP kinase pathway specificity. A pathway-specific scaffold, Bem4p, stabilized Cdc42p levels, which biased Cdc42p function in one MAPK pathway over another. Turnover regulation of Rho GTPases by HSPs and scaffolds provides new dimensions to the regulation of cell polarity and signal-dependent morphogenesis.

scholarly journals Pancytopenia, Recurrent Infection, Poor Wound Healing, Heterotopia of the Brain Probably Associated with A Candidate Novel de Novo CDC42 Gene Defect: Expanding the Molecular and Phenotypic Spectrum

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 294
Author(s):  
Abdulaziz Asiri ◽  
Deemah Alwadaani ◽  
Muhammad Umair ◽  
Kheloud M. Alhamoudi ◽  
Mohammed H. Almuhanna ◽  
...  
Keyword(s):  
Wound Healing ◽  
Molecular Mechanisms ◽  
Rho Gtpase ◽  
De Novo ◽  
Functional Characterization ◽  
Substantial Reduction ◽  
Recurrent Infection ◽  
First Case ◽  
The Brain

CDC42 (cell division cycle protein 42) belongs to the Rho GTPase family that is known to control the signaling axis that regulates several cellular functions, including cell cycle progression, migration, and proliferation. However, the functional characterization of the CDC42 gene in mammalian physiology remains largely unclear. Here, we report the genetic and functional characterization of a non-consanguineous Saudi family with a single affected individual. Clinical examinations revealed poor wound healing, heterotopia of the brain, pancytopenia, and recurrent infections. Whole exome sequencing revealed a de novo missense variant (c.101C > A, p.Pro34Gln) in the CDC42 gene. The functional assays revealed a substantial reduction in the growth and motility of the patient cells as compared to the normal cells control. Homology three-dimensional (3-D) modeling of CDC42 revealed that the Pro34 is important for the proper protein secondary structure. In conclusion, we report a candidate disease-causing variant, which requires further confirmation for the etiology of CDC42 pathogenesis. This represents the first case from the Saudi population. The current study adds to the spectrum of mutations in the CDC42 gene that might help in genetic counseling and contributes to the CDC42-related genetic and functional characterization. However, further studies into the molecular mechanisms that are involved are needed in order to determine the role of the CDC42 gene associated with aberrant cell migration and immune response.

scholarly journals Pathological LSD1 mutations cause HDAC-mediated aberrant gene repression during early cell differentiation

2021 ◽  
Author(s):  
Daria Bunina ◽  
Pierre-Luc Germain ◽  
Alejandro Lopez Tobon ◽  
Nadine Fernandez-Novel Marx ◽  
Christian Arnold ◽  
...  
Keyword(s):  
Stem Cells ◽  
Protein Function ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Differentiated Cells ◽  
Lineage Differentiation ◽  
Lysine Specific Demethylase

Lysine-specific demethylase 1 (LSD1/KDM1A) removes methylation of histone and non-histone substrates, and recruits a repressive chromatin complex. De novo LSD1 mutations impairing protein function lead to a rare neurodevelopmental disorder, but the molecular mechanisms of the pathology are unclear. Using patient-derived fibroblasts, reprogrammed pluripotent stem cells, and differentiated cells, we found over 4000 differentially expressed genes and 68 transcription factors (TFs) whose motif accessibilities changed upon LSD1 mutation. An enhancer-mediated gene regulatory network approach identified impaired transcriptional repressor activity in fibroblast and stem cells, leading to erroneous activation of their target genes. Furthermore, our analysis revealed overall decreases in TF target genes specifically during early lineage differentiation of LSD1 mutant stem cells, likely caused by increased activity of repressive co-factors of LSD1 - histone deacetylases (HDACs). Consistently, HDAC inhibitor restored changes in gene expression including downregulation phenotype. Our findings provide insights into pathogenesis of LSD1 mutations and targets for further therapeutic studies.

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