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1.
BACKGROUND: Planar polarity refers to the asymmetry of a cell within the plane of the epithelium; for example, cells may form hairs that point in a posterior direction, or cilia may beat in one way. This property implies that cells have information about their orientation; we wish to understand the nature of this information. Relevant also is the body plan of insects, which, in the ectoderm and somatic mesoderm, consists of a chain of alternating anterior and posterior compartments - basic units of development with independent cell lineage and subject to independent genetic control.RESULTS: Using the abdomen of adult Drosophila, we have taken genes required for normal polarity and either removed the gene or constitutively expressed it in small clones of cells and observed the effects on polarity. Hitherto, all such studies of polarity genes have not found any difference of behavior between the different compartments. We report here that the three genes, four-jointed, dachsous, and fat, cause opposite effects in anterior and posterior compartments. For example, in anterior compartments, clones ectopically expressing four-jointed reverse the polarity of cells in front of the clone, while, in posterior compartments, they reverse behind the clone. These three genes have been reported by others to be functionally linked.CONCLUSIONS: This discovery impacts on models of how cells read polarity. At the heart of one class of models is the hypothesis that cell polarity is determined by the vector of a morphogen gradient. Here, we present evidence that cell polarity in the abdomen depends on at least two protein gradients (Fj and Ds), each of which is reflected at compartment borders. Consequently, these gradients have opposing slopes in the two compartments. Because all polarized structures made by abdominal cells point posteriorly, we surmise that cells in each compartment are programmed to interpret these protein gradients with opposite signs, pointing up the gradient in one compartment and down the gradient in the other. 相似文献
2.
Planar Cell Polarity (PCP) is an evolutionarily conserved characteristic of animal tissues marked by coordinated polarization of cells or structures in the plane of a tissue. In insect wing epithelium, for instance, PCP is characterized by en masse orientation of hairs orthogonal to its apical-basal axis and pointing along the proximal-distal axis of the organ. Directional cue for PCP has been proposed to be generated by complex sets of interactions amongst three proteins - Fat (Ft), Dachsous (Ds) and Four-jointed (Fj). Ft and Ds are two atypical cadherins, which are phosphorylated by Fj, a Golgi kinase. Ft and Ds from adjacent cells bind heterophilically via their tandem cadherin repeats, and their binding affinities are regulated by Fj. Further, in the wing epithelium, sub-cellular levels of Ft-Ds heterodimers are seen to be elevated at the distal edges of individual cells, prefiguring their PCP. Mechanisms generating this sub-cellular asymmetry of Ft-Ds heterodimer in proximal and distal edges of cells, however, have not been resolved yet. Using a mathematical modeling approach, here we provide a framework for generation of this sub-cellular asymmetry of Ft-Ds heterodimer. First, we explain how the known interactions within Ft-Ds-Fj system translate into sub-cellular asymmetry of Ft-Ds heterodimer. Second, we show that this asymmetric localization of Ft-Ds heterodimer is lost when tissue-level gradient of Fj is flattened, or when phosphorylation of Ft by Fj is abolished, but not when tissue-level gradient of Ds is flattened or when phosphorylation of Ds is abrogated. Finally, we show that distal enrichment of Ds also amplifies Ft-Ds asymmetry. These observations reveal that gradient of Fj expression, phosphorylation of Ft by Fj and sub-cellular distal accumulation of Ds are three critical elements required for generating sub-cellular asymmetry of Ft-Ds heterodimer. Our model integrates the known experimental data and presents testable predictions for future studies. 相似文献
3.
Planar cell polarity in the Drosophila eye is directed by graded Four-jointed and Dachsous expression 总被引:4,自引:0,他引:4
Simon MA 《Development (Cambridge, England)》2004,131(24):6175-6184
Planar cell polarity (PCP) occurs when the cells of an epithelium are polarized along a common axis lying in the epithelial plane. During the development of PCP, cells respond to long-range directional signals that specify the axis of polarization. In previous work on the Drosophila eye, we proposed that a crucial step in this process is the establishment of graded expression of the cadherin Dachsous (Ds) and the Golgi-associated protein Four-jointed (Fj). These gradients were proposed to specify the direction of polarization by producing an activity gradient of the cadherin Fat within each ommatidium. In this report, I test and confirm the key predictions of this model by altering the patterns of Fj, Ds and Fat expression. It is shown that the gradients of Fj and Ds expression provide partially redundant positional information essential for specifying the polarization axis. I further demonstrate that reversing the Fj and Ds gradients can lead to reversal of the axis of polarization. Finally, it is shown that an ectopic gradient of Fat expression can re-orient PCP in the eye. In contrast to the eye, the endogenous gradients of Fj and Ds expression do not play a major role in directing PCP in the wing. Thus, this study reveals that the two tissues use different strategies to orient their PCP. 相似文献
4.
The Fat pathway controls both planar cell polarity (PCP) and organ growth. Fat signaling is regulated by the graded expression of the Fat ligand Dachsous (Ds) and the cadherin-domain kinase Four-jointed (Fj). The vectors of these gradients influence PCP, whereas their slope can influence growth. The Fj and Ds gradients direct the polarized membrane localization of the myosin Dachs, which is a crucial downstream component of Fat signaling. Here we show that repolarization of Dachs by differential expression of Fj or Ds can propagate through the wing disc, which indicates that Fj and Ds gradients can be measured over long range. Through characterization of tagged genomic constructs, we show that Ds and Fat are themselves partially polarized along the endogenous Fj and Ds gradients, providing a mechanism for propagation of PCP within the Fat pathway. We also identify a biochemical mechanism that might contribute to this polarization by showing that Ds is subject to endoproteolytic cleavage and that the relative levels of Ds isoforms are modulated by Fat. 相似文献
5.
Drosophila sensory organ precursor cells (SOPs) divide asymmetrically along the anterior-posterior (a-p) body axis to generate two different daughter cells. Planar Cell Polarity (PCP) regulates the a-p orientation of the SOP division. The localization of the PCP proteins Van Gogh (Vang) and Frizzled (Fz) define anterior and posterior apical membrane domains prior to SOP division. Here, we investigate the relative contributions of Vang, Fz and Dishevelled (Dsh), a membrane-associated protein acting downstream of Fz, in orienting SOP polarity. Genetic and live imaging analyses suggest that Dsh restricts the localization of a centrosome-attracting activity to the anterior cortex and that Vang is a target of Dsh in this process. Using a clone border assay, we provide evidence that the Vang and fz genes act redundantly in SOPs to orient its polarity axis in response to extrinsic local PCP cues. Additionally, we find that the activity of Vang is dispensable for the non-autonomous polarizing activity of fz. These observations indicate that both Vang and Fz act as cues for downstream effectors orienting the planar polarity axis of dividing SOPs. 相似文献
6.
We investigate planar cell polarity (PCP) in the Drosophila larval epidermis. The intricate pattern of denticles depends on only one system of PCP, the Dachsous/Fat system. Dachsous molecules in one cell bind to Fat molecules in a neighbour cell to make intercellular bridges. The disposition and orientation of these Dachsous–Fat bridges allows each cell to compare two neighbours and point its denticles towards the neighbour with the most Dachsous. Measurements of the amount of Dachsous reveal a peak at the back of the anterior compartment of each segment. Localization of Dachs and orientation of ectopic denticles help reveal the polarity of every cell. We discuss whether these findings support our gradient model of Dachsous activity. Several groups have proposed that Dachsous and Fat fix the direction of PCP via oriented microtubules that transport PCP proteins to one side of the cell. We test this proposition in the larval cells and find that most microtubules grow perpendicularly to the axis of PCP. We find no meaningful bias in the polarity of microtubules aligned close to that axis. We also reexamine published data from the pupal abdomen and find no evidence supporting the hypothesis that microtubular orientation draws the arrow of PCP. 相似文献
7.
8.
Signaling via the large protocadherin Fat (Ft), regulated in part by its binding partner Dachsous (Ds) and the Golgi-resident kinase Four-jointed (Fj), is required for a variety of developmental functions in Drosophila. Ft and, to a lesser extent, Ds suppress overgrowth of the imaginal discs from which appendages develop and regulate the Hippo pathway [1-5] (reviewed in [6]). Ft, Ds, and Fj are also required for normal planar cell polarity (PCP) in the wing, abdomen, and eye and for the normal patterning of appendages, including the spacing of crossveins in the wing and the segmentation of the leg tarsus (reviewed in [7-9]). Ft signaling was recently shown to be negatively regulated by the atypical myosin Dachs [10, 11]. We identify here an additional negative regulator of Ft signaling in growth control, PCP, and appendage patterning, the Approximated (App) protein. We show that App encodes a member of the DHHC family, responsible for the palmitoylation of selected cytoplasmic proteins, and provide evidence that App acts by controlling the normal subcellular localization and activity of Dachs. 相似文献
9.
Two pathways regulate planar polarity: the core proteins and the Fat-Dachsous-Four-jointed (Ft-Ds-Fj) system. Morphogens specify complementary expression patterns of Ds and Fj that potentially act as polarizing cues. It has been suggested that Ft-Ds-Fj-mediated cues are weak and that the core proteins amplify them. Another view is that the two pathways act independently to generate and propagate polarity: if correct, this raises the question of how gradients of Ft and Ds expression or activity might be interpreted to provide strong cellular polarizing cues and how such cues are propagated from cell to cell. Here, we demonstrate that the complementary expression of Ds and Fj results in biased Ft and Ds protein distribution across cells, with Ft and Ds accumulating on opposite edges. Furthermore, boundaries of Ft and Ds expression result in subcellular asymmetries in protein distribution that are transmitted to neighboring cells, and asymmetric Ds localization results in a corresponding asymmetric distribution of the myosin Dachs. We show that the generation of subcellular asymmetries of Ft and Ds and the core proteins is largely independent in the wing disc and additionally that ommatidial polarity in the eye can be determined without input from the Ft-Ds-Fj system, consistent with the two pathways acting in parallel. 相似文献
10.
Four-jointed (fj) is required for proximodistal growth and planar polarity in Drosophila tissues. It encodes a predicted type II transmembrane protein with putative signal peptidase sites in its transmembrane domain, and its C terminus is secreted. Fj has therefore been proposed to act as a secreted signalling molecule. We show that Fj protein has a graded distribution in eye and wing imaginal discs, and is largely localised to the Golgi in vivo and in transfected cells. Forms of Fj that are constitutively secreted or anchored in the Golgi were assayed for function in vivo. We find that cleavage and secretion of Fj is not necessary for activity, and that Golgi-anchored Fj has increased activity over wild type. fj has similar phenotypes to those caused by mutations in the cadherin-encoding genes fat (ft) and dachsous (ds). We show that fj interacts genetically with ft and ds in planar polarity and proximodistal patterning. We propose that Fj may act in the Golgi to regulate the activity of Ft and Ds. 相似文献
11.
Bacterial cells are spatiotemporally highly organised with proteins localising dynamically to distinct subcellular regions. Motility in the rod-shaped Myxococcus xanthus cells represents an example of signal-induced spatiotemporal regulation of cell polarity. M. xanthus cells move across surfaces with defined front–rear polarity; occasionally, they invert polarity and, in parallel, reverse direction of movement. The polarity module establishes front–rear polarity between reversals and consists of the Ras-like GTPase MglA and its cognate GEF and GAP, that all localise asymmetrically to the cell poles. The Frz chemosensory system constitutes the polarity inversion module and interfaces with the proteins of the polarity module, thereby triggering their polar repositioning. As a result, the polarity proteins, over time, toggle between the cell poles causing cells to oscillate irregularly. Here, we review recent progress in how front–rear polarity is established by the polarity module and inverted by the Frz system and highlight open questions for future studies. 相似文献
12.
Dragana Antic Jennifer L. Stubbs Kaye Suyama Chris Kintner Matthew P. Scott Jeffrey D. Axelrod 《PloS one》2010,5(2)
Left-right asymmetry in vertebrates is initiated in an early embryonic structure called the ventral node in human and mouse, and the gastrocoel roof plate (GRP) in the frog. Within these structures, each epithelial cell bears a single motile cilium, and the concerted beating of these cilia produces a leftward fluid flow that is required to initiate left-right asymmetric gene expression. The leftward fluid flow is thought to result from the posterior tilt of the cilia, which protrude from near the posterior portion of each cell''s apical surface. The cells, therefore, display a morphological planar polarization. Planar cell polarity (PCP) is manifested as the coordinated, polarized orientation of cells within epithelial sheets, or as directional cell migration and intercalation during convergent extension. A set of evolutionarily conserved proteins regulates PCP. Here, we provide evidence that vertebrate PCP proteins regulate planar polarity in the mouse ventral node and in the Xenopus gastrocoel roof plate. Asymmetric anterior localization of VANGL1 and PRICKLE2 (PK2) in mouse ventral node cells indicates that these cells are planar polarized by a conserved molecular mechanism. A weakly penetrant Vangl1 mutant phenotype suggests that compromised Vangl1 function may be associated with left-right laterality defects. Stronger functional evidence comes from the Xenopus GRP, where we show that perturbation of VANGL2 protein function disrupts the posterior localization of motile cilia that is required for leftward fluid flow, and causes aberrant expression of the left side-specific gene Nodal. The observation of anterior-posterior PCP in the mouse and in Xenopus embryonic organizers reflects a strong evolutionary conservation of this mechanism that is important for body plan determination. 相似文献
13.
Interactions between Fat and Dachsous and the regulation of planar cell polarity in the Drosophila wing 总被引:4,自引:0,他引:4
It was recently suggested that a proximal to distal gradient of the protocadherin Dachsous (Ds) acts as a cue for planar cell polarity (PCP) in the Drosophila wing, orienting cell-cell interactions by inhibiting the activity of the protocadherin Fat (Ft). This Ft-Ds signaling model is based on mutant loss-of-function phenotypes, leaving open the question of whether Ds is instructive or permissive for PCP. We developed tools for misexpressing ds and ft in vitro and in vivo, and have used these to test aspects of the model. First, this model predicts that Ds and Ft can bind. We show that Ft and Ds mediate preferentially heterophilic cell adhesion in vitro, and that each stabilizes the other on the cell surface. Second, the model predicts that artificial gradients of Ds are sufficient to reorient PCP in the wing; our data confirms this prediction. Finally, loss-of-function phenotypes suggest that the gradient of ds expression is necessary for correct PCP throughout the wing. Surprisingly, this is not the case. Uniform levels of ds drive normally oriented PCP and, in all but the most proximal regions of the wing, uniform ds rescues the ds mutant PCP phenotype. Nor are distal PCP defects increased by the loss of spatial information from the distally expressed four-jointed (fj) gene, which encodes putative modulator of Ft-Ds signaling. Thus, while our results support the existence of Ft-Ds binding and show that it is sufficient to alter PCP, ds expression is permissive or redundant with other PCP cues in much of the wing. 相似文献
14.
Separating the adhesive and signaling functions of the Fat and Dachsous protocadherins 总被引:4,自引:0,他引:4
The protocadherins Fat (Ft) and Dachsous (Ds) are required for several processes in the development of Drosophila, including controlling growth of imaginal discs, planar cell polarity (PCP) and the proximodistal patterning of appendages. Ft and Ds bind in a preferentially heterophilic fashion, and Ds is expressed in distinct patterns along the axes of polarity. It has thus been suggested that Ft and Ds serve not as adhesion molecules, but as receptor and ligand in a poorly understood signaling pathway. To test this hypothesis, we performed a structure-function analysis of Ft and Ds, separating their adhesive and signaling functions. We found that the extracellular domain of Ft is not required for its activity in growth, PCP and proximodistal patterning. Thus, ligand binding is not necessary for Ft activity. By contrast, the extracellular domain of Ds is necessary and sufficient to mediate its effects on PCP, consistent with the model that Ds acts as a ligand during PCP. However, we also provide evidence that Ds can regulate growth independently of Ft, and that the intracellular domain of Ds can affect proximodistal patterning, both suggestive of functions independent of binding Ft. Finally, we show that ft mutants or a dominant-negative Ft construct can affect disc growth without changes in the expression of wingless and Wingless target genes. 相似文献
15.
Katharina Nübler-Jung 《Development genes and evolution》1987,196(5):286-289
Summary The insect integument displays planar tissue polarity in the uniform orientation of polarized cuticular structures. In a body segment, for example, the denticles and bristles produced by the constituent epidermal cells point posteriorly. Colchicine can abolish this uniform orientation while still allowing individual cells to form orientated cuticular structures and thereby to express cell polarity. This suggests that an individual cell in a sheet can establish planar polarity without reference to some kind of covert supracellular cue (such as a morphogen gradient) in the epidermis as a whole. The results also indicate that colchicine interferes — directly or indirectly — with the mechanisms involved in aligning the polarity axes of individual cells into a common orientation, thereby generating supracellular or tissue polarity. 相似文献
16.
Atypical cadherins Dachsous (Ds) and Fat coordinate the establishment of planar polarity, essential for the patterning of complex tissues and organs. The precise mechanisms by which this system acts, particularly in cases where Ds and Fat act independently of the ‘core’ frizzled system, are still the subject of investigation. Examining the deployment of the Ds–Fat system in different tissues of the model organism Drosophila, has provided insights into the general mechanisms by which polarity is established and propagated to coordinate outcomes across a field of cells. The Drosophila embryonic epidermis provides a simple model epithelia where the establishment of polarity can be observed from start to finish, and in the absence of proliferation, over a fixed number of cells. Using the asymmetric placement of f-actin during denticle assembly as a read-out of polarity, we examine the requirement for Ds and Fat in establishing polarity across the denticle field. Comparing detailed phenotypic analysis with steady state protein enrichment revealed a spatially restricted requirement for the Ds–Fat system within the posterior denticle field. Ectopic Ds signaling provides evidence for a model whereby Ds acts to asymmetrically enrich Fat in a neighboring cell, in turn polarizing the cell to specify the position of the actin-based protrusions at the cell cortex. 相似文献
17.
The regular array of distally pointing hairs on the mature Drosophila wing is evidence for the fine control of Planar Cell Polarity (PCP) during wing development. Normal wing PCP requires both the Frizzled (Fz) PCP pathway and the Fat/Dachsous (Ft/Ds) pathway, although the functional relationship between these pathways remains under debate. There is strong evidence that the Fz PCP pathway signals twice during wing development, and we have previously presented a Bidirectional-Biphasic Fz PCP signaling model which proposes that the Early and Late Fz PCP signals are in different directions and employ different isoforms of the Prickle protein. The goal of this study was to investigate the role of the Ft/Ds pathway in the context of our Fz PCP signaling model. Our results allow us to draw the following conclusions: (1) The Early Fz PCP signals are in opposing directions in the anterior and posterior wing and converge precisely at the site of the L3 wing vein. (2) Increased or decreased expression of Ft/Ds pathway genes can alter the direction of the Early Fz PCP signal without affecting the Late Fz PCP signal. (3) Lowfat, a Ft/Ds pathway regulator, is required for the normal orientation of the Early Fz PCP signal but not the Late Fz PCP signal. (4) At the time of the Early Fz PCP signal there are symmetric gradients of dachsous (ds) expression centered on the L3 wing vein, suggesting Ds activity gradients may orient the Fz signal. (5) Localized knockdown or over-expression of Ft/Ds pathway genes shows that boundaries/gradients of Ft/Ds pathway gene expression can redirect the Early Fz PCP signal specifically. (6) Altering the timing of ds knockdown during wing development can separate the role of the Ft/Ds pathway in wing morphogenesis from its role in Early Fz PCP signaling. 相似文献
18.
Amoeboid movement is believed to involve a pressure gradient along the cell length, with contractions in the posterior region driving cytoplasmic streaming forward. However, a parallel mechanism has yet to be demonstrated in migrating adhesive cells. To probe the distribution of intracellular forces, we microinjected high molecular weight linear polyacrylamide (PAA) as a passive force sensor into migrating NIH3T3 fibroblasts. Injected PAA appeared as amorphous aggregates that underwent shape change and directional movement in response to differential forces exerted by the surrounding environment. PAA injected into the posterior region moved toward the front, whereas PAA in the anterior region never moved to the posterior region. This preferential forward movement was observed only in migrating cells with a defined polarity. Disruption of myosin II activity by blebbistatin inhibited the forward translocation of PAA while cell migration persisted in a disorganized fashion. These results suggest a myosin II-dependent force gradient in migrating cells, possibly as a result of differential cortical contractions between the anterior and posterior regions. This gradient may be responsible for the forward transport of cellular components and for maintaining the directionality during cell migration. 相似文献
19.
Renuka Raman Clyde Savio Pinto Mahendra Sonawane 《Journal of molecular biology》2018,430(19):3565-3584
Polarity is one of the fundamental properties displayed by living organisms. In metazoans, cell polarity governs developmental processes and plays an essential role during maintenance of forms of tissues as well as their functions. The mechanisms of establishment and maintenance of cell polarity have been investigated extensively in the last two decades. This has resulted in identification of “core cell polarity modules” that control anterior–posterior, front–rear and apical–basal polarity across various cell types. Here, we review how these polarity modules interact closely with the cytoskeleton during establishment and maintenance of cytoskeletal polarity. We further suggest that reciprocal interactions between cell polarity modules and the cytoskeleton consolidate the initial weaker polarity, arising from an external cue, into a committed polarized system. 相似文献
20.
Ascidian prickle regulates both mediolateral and anterior-posterior cell polarity of notochord cells
The ascidian notochord follows a morphogenetic program that includes convergent extension (C/E), followed by anterior-posterior (A/P) elongation [1-4]. As described here, developing notochord cells show polarity first in the mediolateral (M/L) axis during C/E, and subsequently in the A/P axis during elongation. Previous embryological studies [3] have shown that contact with neighboring tissues is essential for directing M/L polarity of ascidian notochord cells. During C/E, the planar cell polarity (PCP) gene products prickle (pk) and dishevelled (dsh) show M/L polarization. pk and dsh colocalize at the notochord cell membranes, with the exception of those in contact with neighboring muscle cells. In the mutant aimless (aim), which carries a deletion in pk, notochord morphogenesis is disrupted, and cell polarization is lost. After C/E, there is a dynamic relocalization of PCP proteins in the notochord cells with dsh localized to the lateral edges of the membrane, and pk and strabismus (stbm) at the anterior edges. An A/P polarity is present in the extending notochord cells and is evident by the position of the nuclei, which in normal embryos are invariably found at the posterior edge of each cell. In the aim mutant, all appearances of A/P polarity in the notochord are lost. 相似文献