Cells migrate collectively in a coordinated manner to accomplish various tasks for development of the organism, from gametogenesis to morphogenesis to organogenesis. Collective cell migration allows whole groups of cells to move toward their final destination most efficiently while maintaining tissue cohesivity and tissue-specific characteristics.
All the while, these cells can transmit signals to each other and effectively navigate the complex and changing environment within the developing embryo. Disruption of the keratin network in the amphibian embryo tells quite a different story than mice about the importance of intermediate filaments in early embryogenesis. Disruption of keratin by either targeting protein expression Heasman et al. Pointing to a role in collective migration events, polarized protrusive cell behavior of the mesoderm is lost in the absence of K8 expression in Xenopus embryos Weber et al.
Collective cell movements are also perturbed in keratin mutant mice, albeit at stages of organogenesis and tissue maintenance. Vimentin plays a role in promoting stemness of mammary epithelial cells which provide the basis for mammary gland growth. Ductal outgrowth is significantly delayed in mammary glands from vimentin knockout mice and the lumen is slightly enlarged Virtakoivu et al.
Both populations of mammary cells are involved in the branching morphogenesis of the tissue. Interestingly during the initial development of the mammary placode in the embryonic mouse, these invasive migratory cells express both K8 and K14 Sun et al.
Only recently have selective promoters for basal mammary epithelial cells become available. Morphogenesis of epidermal and muscle tissue in Caenorhabditis elegans provides a particular elegant example of the interplay between intermediate filaments and mechanotransduction pathways during development. With PIX-1 at the hemidesmosome, Rac is activated, which further stimulates PAK-1 activity and subsequent phosphorylation of intermediate filaments Zhang et al.
Phosphorylation of intermediate filaments through this mechanism drives remodeling and maturation of the hemidesmosome and the associated intermediate filament network Zhang et al. Hemidesmosomes behave as mechanosensors that further relay the tension by activation of specific signaling pathway that promotes epithelial morphogenesis Zhang et al.
Indeed, coordination between the epidermis and muscle cells is absolutely essential to epidermal morphogenesis that elongates the worm, and cytoplasmic intermediate filaments are vital to this process Woo et al. Migration driven by cell-cell adhesions has roles very early in development, even as early as development of gametes. Tension sensing through E-cadherin plays a critical role in controlling directionality of migration of border cells in the Drosophila ovary Cai et al.
As with many collectively migrating cells, asymmetric Rac activity also plays a key role in the steering of these migrating collectives Wang et al. For some time, cytoplasmic intermediate filaments were believed to be absent from many non-chordates including arthropods. Knockdown of this Tm1 isoform impairs border cell migration, unlike knockdown of other Tm1 isoforms. Intermediate filaments are the next frontier for understanding how cells cope with mechanical stimuli and integrate these signals with cellular function.
Current data bolsters the notion that cytoplasmic intermediate filaments provide a unique scaffolding framework that regulates major mechanotransduction events initiated through cellular adhesions.
Moreover, intermediate filaments function in these mechanotransduction processes in a non-redundant manner that cannot be compensated by other cytoskeletal networks during development.
New innovative methods will have to be devised to tackle the details of how intermediate filaments are regulated in terms of turnover, dynamic exchange, and other remodeling events in vivo. Although, various signaling pathway relationships to intermediate filaments have been found, the molecular mechanism by which intermediate filaments effect signaling is not always clear. For a few proteins, direct interaction with intermediate filaments are known to exist. Subcellular compartmentalization of the different intermediate filament polymerization states i.
Intermediate filament filaments and particles may form a differential composite network that, in coordination with the other cytoskeletal elements, endures and responds to changing physical parameters that cells experience during development. Significant headway has been made to investigate the relationship between intermediate filaments and the actin and microtubule networks.
Still, questions remain particularly related to the in vivo functionality of intermediate filament elasticity. In this regard, intermediate filaments could store substantial potential energy and enable cell contractility through a non-actomyosin mechanism. Both actomyosin and intermediate filaments could work cooperatively as dynamic elastic components.
Likewise, nuanced differences between various keratin proteins and vimentin in regulation, turnover rates, and mechanical properties are likely optimized for different cell and tissue-specific functions.
Intermediate filaments as elastic, but resilient, cytoskeletal structures may undergo conformational changes due to mechanical stresses that unmask cryptic binding sites within the polymerized filament. If great enough, these stresses might otherwise rupture a cell or another cytoskeletal component, but intermediate filaments are uniquely suited to cope with these greater forces. For cytoplasmic intermediate filaments, they become a strain sensor- in essence, only permitting certain cell signaling events to occur when strain is applied.
Developmental morphogenesis and cell migration are but two processes for which these signals would be important, yet important ones since dramatic tissue shaping occurs on a rapid timescale. As much as intermediate filaments have historically been touted as the keepers of cellular mechanical integrity, investigating them as dynamic components of cellular mechanosensor complexes is demanded. If we think about different types of adhesions as an interdependent network, then perhaps we can confer a similar thought process to how we think about cytoskeletal networks.
Given the coordination in localization, function, and integration with signal transduction pathways, our longstanding conceptual models of discrete adhesive structures with separate cytoskeletal networks may be long overdue for a re-thinking. As much as we have learned about the role of cell adhesions and actomyosin in force-induced signal transduction in the last decade, the potential exists for an equally robust phase of discovery about intermediate filaments and their role in mechanotransduction during development.
RS and GW shared equally in the conceptual development, literature research, and writing of the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We would like to thank the members of the Weber laboratory, especially Shalaka Paranjpe, Richard Mariani, and Huri Mucahit, for helpful discussions leading to the production of this manuscript. Ackbarow, T. Alpha-helical protein networks are self-protective and flaw-tolerant.
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Presented in Figure 2 is a digital image of the keratin intermediate network found in a rat kangaroo PtK2 line epithelial cell as seen through a fluorescence optical microscope. The extensive intertwined network was labeled with primary antibodies to several cytokeratin proteins, which were then stained with secondary antibodies containing a green fluorescent dye.
The nucleus was counterstained with a blue dye to note its location in relation to the intermediate filament network. Fluorescence microscopy is an important tool that scientists use to examine the structure and function of internal cellular organelles and the cytoskeleton.
As illustrated in Figure 1, intermediate filament monomer peptides are an elongated fibrous class of proteins with a central alpha -helical region capped with globular ends at both the amino and carboxylic acid termini. Two of the monomer units form a coiled-coil dimer that self-associates in an anti-parallel arrangement to form a staggered tetramer, which is the analogous soluble subunit for the globular actin monomer and the tubulin heterodimer existing free in the cytoplasm.
Tetramer units pack together laterally to form a sheet of eight parallel protofilaments that are supercoiled into a tight bundle. Each tightly coiled intermediate filament cross section reveals 32 individual alpha -helical peptides, which renders the filament easy to bend but quite difficult to break, thus accounting for the extreme structural rigidity. Although less is understood about the mechanism of intermediate filament assembly and disassembly, it is clear that some classes are highly dynamic structures with a significant rate of turnover in many cell types.
Mutations in intermediate filament genes lead to a host of rather uncommon diseases. For example, defective keratins in skin tissue lead to a disorder known as epidermolysis bullosa simplex , manifested by skin blisters produced with even a slight mechanical stress. Similar blistering diseases due to keratin mutations in other tissues affect the esophagus, eyes, and mouth. Actin filaments are the smallest type, with a diameter of only about 6 nm, and they are made of a protein called actin.
Intermediate filaments, as their name suggests, are mid-sized, with a diameter of about 10 nm. Unlike actin filaments and microtubules, intermediate filaments are constructed from a number of different subunit proteins.
What Do Microtubules Do? Figure 1. What Do Actin Filaments Do? Figure 2. What Do Intermediate Filaments Do? Figure 4: The structure of intermediate filaments. Intermediate filaments are composed of smaller strands in the shape of rods. How Do Cells Move? The cytoskeleton of a cell is made up of microtubules, actin filaments, and intermediate filaments.
These structures give the cell its shape and help organize the cell's parts. In addition, they provide a basis for movement and cell division. Cell Biology for Seminars, Unit 3. Topic rooms within Cell Biology Close. No topic rooms are there. Or Browse Visually. Student Voices.
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