Forces generated by the actomyosin cytoskeleton are key contributors to many morphogenetic processes. The actomyosin cytoskeleton organises in different types of networks depending on intracellular signals and on cell-cell and cell-extracellular matrix (ECM) interactions. However, actomyosin networks are not static and transitions between them have been proposed to drive morphogenesis. Still, little is known about the mechanisms that regulate the dynamics of actomyosin networks during morphogenesis. This work uses the Drosophila follicular epithelium, real-time imaging, laser ablation and quantitative analysis to study the role of integrins on the regulation of basal actomyosin networks organisation and dynamics and the potential contribution of this role to cell shape. We find that elimination of integrins from follicle cells impairs F-actin recruitment to basal medial actomyosin stress fibers. The available F-actin redistributes to the so-called whip-like structures, present at tricellular junctions, and into a new type of actin-rich protrusions that emanate from the basal cortex and project towards the medial region. These F-actin protrusions are dynamic and changes in total protrusion area correlate with periodic cycles of basal myosin accumulation and constriction pulses of the cell membrane. Finally, we find that follicle cells lacking integrin function show increased membrane tension and reduced basal surface. Furthermore, the actin-rich protrusions are responsible for these phenotypes as their elimination in integrin mutant follicle cells rescues both tension and basal surface defects. We thus propose that the role of integrins as regulators of stress fibers plays a key role on controlling epithelial cell shape, as integrin disruption promotes reorganisation into other types of actomyosin networks, in a manner that interferes with proper expansion of epithelial basal surfaces.
The spectrin cytoskeleton crosslinks actin to the membrane, and although it has been greatly studied in erythrocytes, much is unknown about its function in epithelia. We have studied the role of spectrins during epithelia morphogenesis using the Drosophila follicular epithelium (FE). As previously described, we show that α-Spectrin and β-Spectrin are essential to maintain a monolayered FE, but, contrary to previous work, spectrins are not required to control proliferation. Furthermore, spectrin mutant cells show differentiation and polarity defects only in the ectopic layers of stratified epithelia, similar to integrin mutants. Our results identify α-Spectrin and integrins as novel regulators of apical constriction-independent cell elongation, as α-Spectrin and integrin mutant cells fail to columnarize. Finally, we show that increasing and reducing the activity of the Rho1-Myosin II pathway enhances and decreases multilayering of α-Spectrin cells, respectively. Similarly, higher Myosin II activity enhances the integrin multilayering phenotype. This work identifies a primary role for α-Spectrin in controlling cell shape, perhaps by modulating actomyosin. In summary, we suggest that a functional spectrin-integrin complex is essential to balance adequate forces, in order to maintain a monolayered epithelium.
Summary Stem cells reside in specialized microenvironments or niches that balance stem cell proliferation and differentiation. 1 , 2 The extracellular matrix (ECM) is an essential component of most niches, because it controls niche homeostasis, provides physical support, and conveys extracellular signals. 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 Basement membranes (BMs) are thin ECM sheets that are constituted mainly by Laminins, Perlecan, Collagen IV, and Entactin/Nidogen and surround epithelia and other tissues. 12 Perlecans are secreted proteoglycans that interact with ECM proteins, ligands, receptors, and growth factors such as FGF, PDGF, VEGF, Hedgehog, and Wingless. 13 , 14 , 15 , 16 , 17 , 18 Thus, Perlecans have structural and signaling functions through the binding, storage, or sequestering of specific ligands. We have used the Drosophila ovary to assess the importance of Perlecan in the functioning of a stem cell niche. Ovarioles in the adult ovary are enveloped by an ECM sheath and possess a tapered structure at their anterior apex termed the germarium. The anterior tip of the germarium hosts the germline niche, where two to four germline stem cells (GSCs) reside together with a few somatic cells: terminal filament cells (TFCs), cap cells (CpCs), and escort cells (ECs). 19 We report that niche architecture in the developing gonad requires trol, that niche cells secrete an isoform-specific Perlecan-rich interstitial matrix, and that D E-cadherin-dependent stem cell-niche adhesion necessitates trol . Hence, we provide evidence to support a structural role for Perlecan in germline niche establishment during larval stages and in the maintenance of a normal pool of stem cells in the adult niche.
Muscle development is a multistep process that involves cell specification, myoblast fusion, myotube migration, and attachment to the tendons. In spite of great efforts trying to understand the basis of these events, little is known about the molecular mechanisms underlying myotube migration. Knowledge of the few molecular cues that guide this migration comes mainly from studies in Drosophila. The migratory process of Drosophila embryonic muscles involves a first phase of migration, where muscle progenitors migrate relative to each other, and a second phase, where myotubes migrate searching for their future attachment sites. During this phase, myotubes form extensive filopodia at their ends oriented preferentially toward their attachment sites. This myotube migration and the subsequent muscle attachment establishment are regulated by cell adhesion receptors, such as the conserved proteoglycan Kon-tiki/Perdido. Laminins have been shown to regulate the migratory behavior of many cell populations, but their role in myotube migration remains largely unexplored. Here, we show that laminins, previously implicated in muscle attachment, are indeed required for muscle migration to tendon cells. Furthermore, we find that laminins genetically interact with kon-tiki/perdido to control both myotube migration and attachment. All together, our results uncover a new role for the interaction between laminins and Kon-tiki/Perdido during Drosophila myogenesis. The identification of new players and molecular interactions underlying myotube migration broadens our understanding of muscle development and disease.
The spectrin cytoskeleton crosslinks actin to the membrane, and although it has been greatly studied in erythrocytes, much is unknown about its function in epithelia. We have studied the role of spectrins during epithelia morphogenesis using the Drosophila follicular epithelium (FE). As previously described, we show that α-Spectrin and β-Spectrin are essential to maintain a monolayered FE, but, contrary to previous work, spectrins are not required to control proliferation. Furthermore, spectrin mutant cells show differentiation and polarity defects only in the ectopic layers of stratified epithelia, similar to integrin mutants. Our results identify α-Spectrin and integrins as novel regulators of apical constriction-independent cell elongation, as α-Spectrin and integrin mutant cells fail to columnarize. Finally, we show that increasing and reducing the activity of the Rho1-Myosin II pathway enhances and decreases multilayering of α-Spectrin cells, respectively. Similarly, higher Myosin II activity enhances the integrin multilayering phenotype. This work identifies a primary role for α-Spectrin in controlling cell shape, perhaps by modulating actomyosin. In summary, we suggest that a functional spectrin-integrin complex is essential to balance adequate forces, in order to maintain a monolayered epithelium.
29Forces generated by the actomyosin cytoskeleton are key contributors to the 30 generation of tissue shape. Within the cell, the actomyosin cytoskeleton organizes in 31 different types of networks, each of them performing distinct roles. In addition, 32 although they normally localize to precise regions of the cells, they are rarely 33 independent and often their dynamics influence each other. In fact, the reorganization of 34 a given structure can promote the formation of another, conversions that govern many 35 morphogenetic processes. In addition, maintenance of a specific actomyosin network 36 organization in a differentiated tissue might be equally important. Failure to do so could 37 lead to undesired cell state transitions, which in turn would have drastic consequences 38 on the homeostasis of the tissue. Still, little is known about the mechanisms that ensure 39 controlled transitions between actomyosin networks during morphogenesis or their 40 maintenance in a differentiated tissue. Here, we use the Drosophila follicular epithelium 41 to show that cell-ECM interactions mediated by integrins are necessary for the 42 establishment and maintenance of the different actomyosin networks present in these 43 epithelial cells. Elimination of integrins in a group of follicle cells results in changes in 44 the F-actin levels and physical properties of their intracellular actomyosin networks. 45Integrin mutant follicle cells have reduced number of basal stress fibers. They also show 46 increased cortical F-actin levels and tension, which interferes with proper basal surface 47 growth. Finally, clonal elimination of integrins also triggers non-autonomous 48 behavioural changes in neighbouring wild types cells, which now reorganize their actin 49 cytoskeleton and spread and overlay the mutant ones. Based on these results, we 50propose that cell-ECM interactions mediated by integrins regulate epithelia 51 morphogenesis and homesostasis by preserving the different types of intracellular actin 52 networks. 53 54 55 56 57 58 59 60 61 62 Forces generated by F-actin networks are important contributors to the generation of 64 cell and tissue shape. The architecture and mechanical properties of the F-actin network 65 are modulated by myosin II motors and actin binding proteins (reviewed in 1 . The 66 molecular composition of contractile actin networks and bundles is highly conserved 67 among eukaryotic species 2 . Nevertheless, their organization and dynamics change 68 across different cell types, their position within the cell and the differentiation state of 69 the cell. 70 There are two main ways in which actomyosin networks can be organized within 71 the cell, as cortical two-dimensional meshworks below the plasma membrane or as 72 stress-fibers. Studies over the last decade have assigned distinct roles for these two 73 types of networks. Thus, while pulsatile contraction of cortical actomyosin meshworks 74 has been mainly implicated in the cell shape changes underlying key morphogenetic 75 processes, such as gastrulatio...
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