Epithelial development dictates the shape of an organism. The metamorphic development of a Drosophila leg precursor into an adult leg is a well‐defined example of epithelial morphogenesis that can be analyzed from the perspectives of genetics and molecular and cell biology. The steroid hormone 20‐hydroxyecdysone induces and regulates the entire process. Mutants affecting Drosophila leg morphogenesis characteristically have short thick legs (the malformed phenotype) resulting from a failure to execute normal cell shape changes at a specific (...) stage of development. Mutations that cause the malformed phenotype have already led to the identification and cloning of genes encoding transcription factors, a transmembrane serine protease presumably required for modification of the apical extracellular matrix, and components of the contractile cytoskeleton and adherens junctions. All of these products are required for the execution of normal changes in leg cell shape. (shrink)

A theoretical model is presented for pattern formation in an epithelium. The epithelial model consists of a thin, incompressible, viscoelastic membrane on an elastic foundation (substrate), with the component cells assumed to have active contractile properties similar to those of smooth muscle. The analysis includes the effects of large strains and material nonlinearity, and the governing equations were solved using finite differences. Deformation patterns form when the cells activate while lying on the descending limb of their total (active + (...) passive) stress-stretch curve. Various one-dimensional and two-dimensional simulations illustrate the effects of spatial and temporal variations in passive stiffness, as well as the effects of foundation stiffness and stretch activation. The model can be used to examine the mechanical aspects of pattern formation in morphogenetic processes such as angiogenesis and myocardial trabeculation. (shrink)

The c‐ros, c‐met and c‐neu genes encode receptor‐type tyrosine kinases and were originally identified because of their oncogenic potential. However, recent progress in the analysis of these receptors and their respective ligands indicate that they do not mediate exclusively mitogenic signals. Rather, they can induce cell movement, differentiation or morphogenesis of epithelial cells in culture. Interestingly, the discussed receptors are expressed in embryonal epithelia, whereas direct and indirect evidence shows that the corresponding ligands are produced in mesenchymal cells. (...) In development, signals given by mesenchymal cells are major driving forces for differentiation and morphogenesis of epithelia; embryonal epithelia are generally unable to differentiate without the appropriate mesenchymal factors. The observed activities of these receptor/ligand systems in cultured cells and their expression patterns indicate that they regulate epithelial differentiation and morphogenesis also during embryogenesis and suggest thus a molecular basis for mesenchymal epithelial interactions. (shrink)

Cell morphogenesis encompasses all processes required to establish a three-dimensional cell shape. Cells acquire the architecture specific to their developmental context by using the spatial information provided by internal or external cues. As a response to these signals, cells become reorganized and establish functionally distinct subcellular domains that ultimately lead to morphological changes. In its simplest form, cell morphogenesis results in the establishment of asymmetry along one axis, a cell polarity. Although cell polarity has been studied intensively in (...) budding yeast and epithelial cells, little is known about more complex modes of cell morphogenesis involving multiple axes. In this review we compare the regulation of cell morphogenesis of different genetically well-characterized cell types in Arabidopsis thaliana. BioEssays 20:20–29, 1998. © 1998 John Wiley & Sons, Inc. (shrink)

Early morphogenesis of mouse submandibular gland provides an excellent model for the formation of epithelial lobules as a consequence of epithelial‐mesenchymal interactions. Both proteoglycans and a glycosaminoglycan, high molecular weight components which contain amino‐sugars and hexuronic acids, seem to be important in maintaining the lobular structure through the formation of epithelial basal lamina. Collagen also appears to play a crucial role in this morphogenesis. By visualizing the distribution of collagen fibrils and by changing the concentration (...) of collagen in the gland, we have developed a new hypothesis which emphasizes the mechanical role of mesenchyme in epithelial cleft formation. Precise mechanisms for the involvement of these molecules have not been elucidated, yet it is now clear that knowledge of the function of the extracellular matrix components is a prerequisite for understanding the epithelial‐mesenchymal interactions. (shrink)

Branching morphogenesis of epithelia is an important mechanism in mammalian development. The last decade has seen the identification of many signalling pathways and intracellular mechanisms that control epithelial branching. Tissue‐level mechanisms that space new branches out have, however, remained an unsolved problem. A recent publication by Nelson et al.1 suggests—if extrapolation from their novel and abstract culture system is valid—that branches may be spaced out by a system of mutual inhibition based on diffusion of TGFβ. Such a system (...) would allow a developing tree to arrange itself, without detailed genetic specification, by adaptive self‐organization. BioEssays 29: 205–207, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Early morphogenesis of mouse submandibular gland provides an excellent model for the formation of epithelial lobules as a consequence of epithelial‐mesenchymal interactions. Both proteoglycans and a glycosaminoglycan, high molecular weight components which contain amino‐sugars and hexuronic acids, seem to be important in maintaining the lobular structure through the formation of epithelial basal lamina. Collagen also appears to play a crucial role in this morphogenesis. By visualizing the distribution of collagen fibrils and by changing the concentration (...) of collagen in the gland, we have developed a new hypothesis which emphasizes the mechanical role of mesenchyme in epithelial cleft formation. Precise mechanisms for the involvement of these molecules have not been elucidated, yet it is now clear that knowledge of the function of the extracellular matrix components is a prerequisite for understanding the epithelial‐mesenchymal interactions. (shrink)

Cell morphogenesis encompasses all processes required to establish a three-dimensional cell shape. Cells acquire the architecture specific to their developmental context by using the spatial information provided by internal or external cues. As a response to these signals, cells become reorganized and establish functionally distinct subcellular domains that ultimately lead to morphological changes. In its simplest form, cell morphogenesis results in the establishment of asymmetry along one axis, a cell polarity. Although cell polarity has been studied intensively in (...) budding yeast and epithelial cells, little is known about more complex modes of cell morphogenesis involving multiple axes. In this review we compare the regulation of cell morphogenesis of different genetically well-characterized cell types in Arabidopsis thaliana. BioEssays 20:20–29, 1998. © 1998 John Wiley & Sons, Inc. (shrink)

Our understanding of epithelial development in Drosophila has been greatly improved in recent years. Two key regulators of epithelial polarity, Crumbs and DE‐cadherin, have been studied at the genetic and molecular levels and a number of additional genes are being analyzed that contribute to the differentiation of epithelial cell structure. Epithelial architecture has a profound influence on morphogenetic movements, patterning and cell‐type determination. The combination of embryological and genetic/molecular tools in Drosophila will help us to elucidate (...) the complex events that determine epithelial cell structure and how they relate to morphogenesis and other developmental processes. (shrink)

Reactive oxygen species (ROS) are highly reactive molecules produced in cells. So far, they have mostly been connected to diseases and pathological conditions. More recent results revealed a somewhat unexpected role of ROS in control of developmental processes. In this review, we elaborate on ROS in development, focussing on their connection to epithelial tissue morphogenesis. After briefly summarising unique characteristics of epithelial cells, we present some characteristic features of ROS species, their production and targets, with a focus (...) on proteins important for epithelial development and function. Finally, we provide examples of regulation of epithelial morphogenesis by ROS, and also of developmental genes that regulate the overall redox status. We conclude by discussing future avenues of research that will further elucidate ROS regulation in epithelial development. (shrink)

It is universally accepted that genetic control over basic aspects of cell and molecular biology is the primary organizing principle in development and homeostasis of living systems. However, instances do exist where important aspects of biological order arise without explicit genetic instruction, emerging instead from simple physical principles, stochastic processes, or the complex self‐organizing interaction between random and seemingly unrelated parts. Being mostly resistant to direct genetic dissection, the analysis of such emergent processes falls into a grey area between mathematics, (...) physics and molecular cell biology and therefore remains very poorly understood. We recently proposed a mathematical model predicting the emergence of a specific non‐Gaussian distribution of polygonal cell shapes from the stochastic cell division process in epithelial cell sheets; this cell shape distribution appears to be conserved across a diverse set of animals and plants.1 The use of such topological models to study the process of cellular morphogenesis has a long history, starting almost a century ago, and many insights from those original works influence current experimental studies. Here we review current and past literature on this topic while exploring some new ideas on the origins and implications of topological order in proliferating epithelia. BioEssays 30:260–266, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Morphogenesis is a key process in developmental biology. An important issue is the understanding of the generation of shape and cellular organisation in tissues. Despite of their great diversity, morphogenetic processes share common features. This work is an attempt to describe this diversity using the same formalism based on a cellular description. Tissue is seen as a multi-cellular system whose behaviour is the result of all constitutive cells dynamics. Morphogenesis is then considered as a spatiotemporal organization of cells (...) activities. We show how this formalism relies on Reaction–Diffusion/Positional Information approach and how it permits to generalize its modelling possibilities. Three quite different applications for concrete morphogenetic processes are presented. The first one is a model for epithelial invagination, the second is a model of cellular differentiation by local cell–cell signalling. The last example is the secondary radial growth of conifer trees. From the mathematical point of view, different modelling tools are used according to the specificity of each process. (shrink)

It has been convincingly shown that peptides play important roles in the regulation and maintenance of a variety of tissues and organs in living animals. However, little is known concerning the potential role of peptides as signaling molecules in developmental processes. In Hydra, there is circumstantial evidence that small diffusible molecules act as morphogens in the regulation of patterning processes. In order to view the entire spectrum of peptide signaling molecules, we initiated a project aiming at the systematic identification of (...) peptide signaling molecules in Hydra. In this review, we describe three peptide signaling molecules and one family of peptides that function as signaling molecules in the processes of axial pattern formation and neuron differentiation in Hydra. These peptides are produced by epithelial cells and are therefore termed “epitheliopeptides”. We discuss the importance of epitheliopeptides in developmental processes within a subset of hydrozoans. (shrink)

The change in shape of the C. elegans embryo from an ovoid ball of cells into a worm-shaped larva is driven by three events within the cells of the hypodermis (epidermis): (1) intercalation of two rows of dorsal cells, (2) enclosure of the ventral surface by hypodermis, and (3) elongation of the embryo. While the behavior of the hypodermal cells involved in each of these processes differs dramatically, it is clear that F-actin and microtubules have essential functions in each of (...) these processes, whereas contraction of actomyosin structures appears to be involved specifically in elongation. Molecular analysis of these processes is revealing components specific to C. elegans as well as components found in other systems. Since C. elegans hypodermal cells demonstrate dramatically different behaviors during intercalation, enclosure and elongation, the study of cytoskeletal dynamics in these processes may reveal both unique and conserved activities during distinct epithelial morphogenetic movements. BioEssays 23:12–23, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Actomyosin (actin‐myosin II complex)‐mediated contractile forces are central to the generation of multifaceted uni‐ and multi‐cellular material properties and dynamics such as cell division, migration, and tissue morphogenesis. In the present article, we summarize our recent researches addressing molecular mechanisms that ensure actomyosin‐mediated directional cell–cell junction remodeling, either shortening or extension, driving cell rearrangement for epithelial morphogenesis. Genetic perturbation clarified two points concerning cell–cell junction remodeling: an inhibitory mechanism against negative feedback in which actomyosin contractile forces, which (...) are well known to induce cell–cell junction shortening, can concomitantly alter actin dynamics, oppositely leading to perturbation of the shortening; and tricellular junctions as a point that organizes extension of new cell–cell junctions after shortening. These findings highlight the notion that cells develop underpinning mechanisms to transform the multi‐tasking property of actomyosin contractile forces into specific and proper cellular dynamics in space and time. (shrink)

During gestation, fetomaternal exchange occurs in the villous tree (labyrinth) of the placenta. Development of this structure depends on tightly coordinated cellular processes of branching morphogenesis and differentiation of specialized trophoblast cells. The basal chorionic trophoblast (BCT) cell layer that localizes next to the chorioallantoic interface is of critical importance for labyrinth morphogenesis in rodents. Gcm1‐positive cell clusters within this layer initiate branching morphogenesis thereby guiding allantoic fetal blood vessels towards maternal blood sinuses. Later these cells differentiate (...) and contribute to the syncytiotrophoblast of the fetomaternal barrier. Additional cells within the BCT layer sustain continued morphogenesis, possibly through a repopulating progenitor population. Several mouse mutants highlight the importance of a structurally intact BCT epithelium, and a growing number of studies addresses its patterning and epithelial architecture. Here, we review and discuss emerging concepts in labyrinth development focussing on the biology of the BCT cell layer. (shrink)

Dorsal closure (DC), the closure of a hole in the dorsal epidermis of Drosophila embryos by the joining of opposing epithelial cell sheets, has been used as a model process to study the molecular and cellular mechanisms underlying epithelial spreading and wound healing. Recent studies have provided novel insights into how different tissues function cooperatively in this process. Specifically, they demonstrate a critical function of the epidermis surrounding the hole in modulating the behavior of the amnioserosa cells inside. (...) These findings shed light not only on the mechanisms by which the behavior of different tissues is coordinated during DC, but also on the general mechanisms by which tissues interact to trigger global morphogenesis, an essential but yet poorly explored aspect of embryogenesis. (shrink)

Growth and morphogenesis in the mammary gland depend on locally derived growth factors such as those in the epidermal growth factor (EGF) superfamily. Cripto-1 (CR-1, human; Cr-1, mouse)—also known as teratocarcinoma-derived growth factor-1—is a novel EGF-related protein that induces branching morphogenesis in mammary epithelial cells both in vitro and in vivo and inhibits the expression of various milk proteins. In the mouse, Cr-1 is expressed in the growing terminal end buds in the virgin mouse mammary gland and (...) expression increases during pregnancy and lactation. Cr-1/CR-1 is overexpressed in mouse and human mammary tumors and inappropriate overexpression of Cr-1 in mouse mammary epithelial cells can lead to the clonal expansion of ductal hyperplasias. Taken together, this evidence suggests that Cr-1/CR-1 performs a role in normal mammary gland development and that it might contribute to the early stages of mouse mammary tumorigenesis and the pathobiology of human breast cancer. BioEssays 1999;21:61–70. Published 1999 John Wiley & Sons, Inc. (shrink)

Formation of branching epithelial trees from unbranched precursors is a common process in animal organogenesis. In humans, for example, this process gives rise to the airways of the lungs, the urine‐collecting ducts of the kidneys and the excretory epithelia of the mammary, prostate and salivary glands. Branching in these different organs, and in different animal classes and phyla, is morphologically similar enough to suggest that they might use a conserved developmental programme, while being dissimilar enough not to make it (...) obviously certain that they do. In this article, I review recent discoveries about the molecular regulation of branching morphogenesis in the best‐studied systems, and present evidence for and against the idea of there being a highly conserved mechanism. Overall, I come to the tentative conclusion that key mechanisms are highly conserved, at least within vertebrates, but acknowledge that more work needs to be done before the case is proved beyond reasonable doubt. BioEssays 24:937–948, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Unlike inert objects, organisms and their cells have the ability to initiate activity by themselves and thus change their properties or states even in the absence of an external cause. This crucial difference led us to search for principles suitable for the study organisms. We propose that cells follow the default state of proliferation with variation and motility, a principle of biological inertia. This means that in the presence of sufficient nutrients, cells will express their default state. We also propose (...) a principle of variation that addresses two central features of organisms, variation and historicity. To address interdependence between parts, we use a third principle, the principle of organization, more specifically, the notion of the closure of constraints. Within this theoretical framework, constraints are specific theoretical entities defined by their relative stability with respect to the processes they constrain. Constraints are mutually dependent in an organized system and act on the default state.Here we discuss the application and articulation of these principles for mathematical modeling of morphogenesis in a specific case, that of mammary ductal morphogenesis, with an emphasis on the default state. Our model has both a biological component, the cells, and a physical component, the matrix that contains collagen fibers. Cells are agents that move and proliferate unless constrained; they exert mechanical forces that act (i) on collagen fibers and (ii) on other cells. As fibers are organized, they constrain the cells’ ability to move and to proliferate. This model exhibits a circularity that can be interpreted in terms of the closure of constraints. Implementing our mathematical model shows that constraints to the default state are sufficient to explain the formation of mammary epithelial structures. Finally, the success of this modeling effort suggests a stepwise approach whereby additional constraints imposed by the tissue and the organism can be examined in silico and rigorously tested by in vitro and in vivo experiments, in accordance with the organicist perspective we embrace. (shrink)

The extracellular domains of several integral membrane proteins are released from the cell surface by a group of enzymes known as “sheddases” through a process called “ectodomain shedding”. Because many transmembrane growth and differentiation factors, including members of the epidermal growth factor (EGF) family that play a crucial role in development, require ectodomain shedding for proper action in vivo, proteolysis is now viewed as a regulatory mechanism in the developing embryos. Two recent reports by Zhao et al. provide evidence for (...) the role of cell surface proteolysis by an ADAM (a disintegrin and metalloprotease) in the development of murine lung.(1,2) Inhibition of tumor necrosis factor‐α converting enzyme (TACE, ADAM17) by the hydroxamic acid‐based metalloprotease inhibitor (TAPI), (1) or a targeted mutation in Zn2+‐binding domain of TACE, (2) disrupts two essential epithelial functions in lung development: branching morphogenesis and cytodifferentiation. Evidence for the role of ADAMs as sheddases in development and growth factor signaling is discussed. BioEssays 24:8–12, 2002. © 2002 John Wiley & Sons, Inc. (shrink)

Villin, a calcium‐regulated actin‐binding protein, modulates the structure and assembly of actin filaments in vitro. It is organized into three domains, the first two of which are homologous. Villin is mainly produced in epithelial cells that develop a brush border and which are responsible for nutrient uptake. Expression of the villin structural gene is precisely regulated during mouse embryogenesis and is restricted in adults, to certain epithelia of the gastrointestinal and urogenital tracts. The function of villin has been assessed (...) by transfecting CV1 cells with a human cDNA encoding wild‐type villin or mutant villin. Synthesis of large amounts of villin in cells which do not normally produce this protein induces the growth of microvilli on the cell surface and the redistribution of F‐actin, concomitant with the disappearance of stress fibers. The complete villin sequence is required for the morphogenic effect. These results suggest that villin plays a key role in the morphogenesis of microvilli. (shrink)

The mutations that cause many forms of inherited retinal degenerations have been identified, yet the mechanisms by which these mutations lead to death of photoreceptor cells of the retina are not completely understood. Investigations of the pathways from mutation to retinal degeneration have focused on spontaneous and engineered animal models of disease. Based on the studies performed to date, four major categories of degeneration mechanism can be identified. These include disruption of photoreceptor outer segment morphogenesis, metabolic overload, dysfunction of (...) retinal pigment epithelial cells, and chronic activation of phototransduction. Future investigations will likely identify additional mechanisms of photoreceptor damage. This review will summarize what has been learned from studying animal models of non-syndromic inherited retinal degenerations. BioEssays 23:605–618, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Planar cell polarity (PCP) refers to the polarization of a field of cells within the plane of a cell sheet. This form of polarization is required for diverse cellular processes in vertebrates, including convergent extension (CE), the establishment of PCP in epithelial tissues and ciliogenesis. Perhaps the most distinct example of vertebrate PCP is the uniform orientation of stereociliary bundles at the apices of sensory hair cells in the mammalian auditory sensory organ. The establishment of PCP in the mammalian (...) cochlea occurs concurrently with CE in this ciliated epithelium, therefore linking three cellular processes regulated by the vertebrate PCP pathway in the same tissue and emerging as a model system for dissecting PCP signaling. This review summarizes the morphogenesis of this model system to assist the interpretation of the emerging data and proposes molecular mechanisms underlying PCP signaling in vertebrates. BioEssays 29: 120–132, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

During development of the anterior eye segment, cells that originate from the surface epithelium or the neuroepithelium need to interact with mesenchymal cells, which predominantly originate from the neural crest. Failures of proper interaction result in a complex of developmental disorders such Peters' anomaly, Axenfeld–Rieger's syndrome or aniridia. Here we review the role of transcription factors that have been identified to be involved in the coordination of anterior eye development. Among these factors is PAX6, which is active in both (...) class='Hi'>epithelial and mesenchymal cells during ocular development, albeit at different doses and times. We propose that PAX6 is a key element that synchronizes the complex interaction of cell types of different origin, which are all needed for proper morphogenesis of the anterior eye. We discuss several molecular mechanisms that might explain the effects of haploinsufficiency of PAX6 and other transcription factors, and the broad variation of the resulting phenotypes. BioEssays 26:374–386, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Efforts from diverse disciplines, including evolutionary studies and biomechanical experiments, have yielded new insights into the genetic, signaling, and mechanical control of tooth formation and functions. Evidence from fossils and non‐model organisms has revealed that a common set of genes underlie tooth‐forming potential of epithelia, and changes in signaling environments subsequently result in specialized dentitions, maintenance of dental stem cells, and other phenotypic adaptations. In addition to chemical signaling, tissue forces generated through epithelial contraction, differential growth, and skeletal constraints (...) act in parallel to shape the tooth throughout development. Here recent advances in understanding dental development from these studies are reviewed and important gaps that can be filled through continued application of evolutionary and biomechanical approaches are discussed. (shrink)

Graphical AbstractA cell translocation mechanism displaces sporadic mutant cells from normal, suppressive epithelial environment during early steps of tumor initiation. This epithelial cell translocation process exerts a selective pressure on early mutant cells to survive and grow in new microenvironment outside of their native niches.

Epithelial hair follicle stem cells (eHFSCs) are required to generate, maintain and renew the continuously cycling hair follicle (HF), supply cells that produce the keratinized hair shaft and aid in the reepithelialization of injured skin. Therefore, their study is biologically and clinically important, from alopecia to carcinogenesis and regenerative medicine. However, human eHFSCs remain ill defined compared to their murine counterparts, and it is unclear which murine eHFSC markers really apply to the human HF. We address this by reviewing (...) current concepts on human eHFSC biology, their immediate progeny and their molecular markers, focusing on Keratin 15 and 19, CD200, CD34, PHLDA1, and EpCAM/Ber‐EP4. After delineating how human eHFSCs may be selectively targeted experimentally, we close by defining as yet unmet key challenges in human eHFSC research. The ultimate goal is to transfer emerging concepts from murine epithelial stem cell biology to human HF physiology and pathology. (shrink)

Cells can transit between a range of stable epithelial and mesenchymal states and this has allowed the evolution of complex body forms. Epithelial to mesenchymal transition (EMT) and its reverse, mesenchymal to epithelial transition (MET), occur sequentially in development and organogenesis. EMT often accompanies transitions between stem‐like cells and their more differentiated progeny, as occurs at gastrulation, although the relevance of this had not been clarified. New findings from the cancer and cell reprogramming fields suggest that EMT (...) and MET can act as essential portals to stem cell character. Here, we review these findings in the broader context of EMT and MET with emphasis on stem cell biology. Using the heart as an example, we also explore the potential role of EMT/MET in organ regeneration. Understanding EMT and MET at a network level will give us new tools to probe stem cell character and enhance tissue repair. (shrink)

We hypothesize that aspects of animal multicellularity originated before the divergence of metazoans from fungi and social amoebae. Polarized epithelial tissues are a defining feature of metazoans and contribute to the diversity of animal body plans. The recent finding of a polarized epithelium in the non‐metazoan social amoeba Dictyostelium discoideum demonstrates that epithelial tissue is not a unique feature of metazoans, and challenges the traditional paradigm that multicellularity evolved independently in social amoebae and metazoans. An alternative view, presented (...) here, is that the common ancestor of social amoebae, fungi, and animals spent a portion of its life cycle in a multicellular state and possessed molecular machinery necessary for forming an epithelial tissue. Some descendants of this ancestor retained multicellularity, while others reverted to unicellularity. This hypothesis makes testable predictions regarding tissue organization in close relatives of metazoans and provides a novel conceptual framework for studies of early animal evolution.Editor's suggested further reading in BioEssays Searching for Eve: Basal metazoans and the evolution of multicellular complexity Abstract. (shrink)

The expression of epithelial cell adhesion and cytoskeletal genes is orchestrated by an apparently unique set of rules. No tissue‐specific transactivator proteins have been found to drive them; only ubiquitous factors are utilized. In non‐epithelial cells, they are actively repressed. Moreover, it was recently found that a single protein (adenovirus E1a) coordinately represses non‐epithelial genes while inducing epithelial genes. A simple model is offered to explain how epithelial gene expression is coordinated. Under this model, the (...) epithelial cell gene expression program is a transcriptional ‘default’; that is, it occurs in the absence of tissue‐specific transactivation. Conversion to this default requires only that mesenchymal transactivators are not expressed, or that central ‘integrator’ proteins are inactive. In their absence, mesenchymal gene expression cannot occur. Moreover, because the repressors cease to be expressed, the epithelial genes are induced. Oncogenes generally cause the breakdown of the epithelial phenotype ‐ generating carcinomas ‐ so genes such as E1a that cause epithelial conversion may prove useful for both understanding and controlling cancer. (shrink)

The YAP/TAZ family of transcriptional co‐activators drives cell proliferation in epithelial tissues and cancers. Yet, how YAP and TAZ are physiologically regulated remains unclear. Here we review recent reports that YAP and TAZ act primarily as sensors of epithelial cell polarity, being inhibited when cells differentiate an apical membrane domain, and being activated when cells contact the extracellular matrix via their basal membrane domain. Apical signalling occurs via the canonical Crumbs/CRB‐Hippo/MST‐Warts/LATS kinase cascade to phosphorylate and inhibit YAP/TAZ. Basal (...) signalling occurs via Integrins and Src family kinases to phosphorylate and activate YAP/TAZ. Thus, YAP/TAZ is localised to the nucleus in basal stem/progenitor cells and cytoplasm in differentiated squamous cells or columnar cells. In addition, other signals such as mechanical forces, tissue damage and possibly receptor tyrosine kinases (RTKs) can influence MST‐LATS or Src family kinase activity to modulate YAP/TAZ activity. (shrink)

This book, the last volume in the Social Morphogenesis series, examines whether or not a Morphogenic society can foster new modes of human relations that could exercise a form of 'relational steering', protecting and promoting a nuanced version of the good life for all. It analyses the way in which the intensification of morphogenesis and the diminishing of morphostasis impact upon human flourishing. The book links intensified morphogenesis to promoting human flourishing based on the assumption that new (...) opportunities open up novel experiences, skills, and modes of communication that appeal to talents previously lacking any outlet or recognition. It proposes that equality of opportunity would increase as ascribed characteristics diminished in importance, and it could be maintained as the notion of achievement continued to diversify. Digitalization has opened the cultural 'archive' for more to explore and, as it expands exponentially, so do new complementary compatibilities whose development foster yet further opportunities. If more people can do more of what they do best, these represent stepping stones towards the 'good life' for more of them. (shrink)

Apoptosis is an essential part of the normal cellular phenotype repertoire. In the absence of appropriate survival factors, apoptosis is activated through specific signalling cassettes. Epithelia form distinctive three‐dimensional cohesive structures that depend on adhesive interactions in order for these tissues to carry out their specialised roles, such as secretion and reproduction. The cellular programme that triggers apoptosis in epithelial cells has not yet been shown to differ from that in other cell types, yet the unique characteristics of epithelia (...) endow them with specific determinants for survival. In particular, cell‐matrix and cell‐cell interactions are required to prevent entry of epithelial cells into apoptosis, and soluble factors that have profound effects on epithelia, such as steroid hormones or hepatocyte growth factor, also influence their survival. The regenerative capacity of certain epithelia is controlled by intrinsic expression of survival genes within stem cell populations, and may regulate the susceptibility of different epithelial tissues to undergo carcinogenesis. (shrink)

The integrin family was originally described as a family of adhesion receptors, utilized by cells for attachment to and migration across components of the extracellular matrix. Epithelial cells in adult tissues are generally stationary cells, but these cells nevertheless express several different integrins. This review will discuss the evidence that integrins on epithelial cells are also likely to function as signaling molecules, allowing these cells to detect attachment or detachment, and changes in the local composition of ligands. Signals (...) initiated by integrins appear to modulate epithelial cell differentiation, proliferation, survival, and gene expression. Because the local concentration of integrin ligands is altered by injury, inflammation, and remodeling, signals initiated through integrins are likely to play important roles in the responses of epithelial cells to each of these processes. (shrink)

This contributed volume aims to reconsider the concept of individuation, clarifying its articulation with respect to contemporary problems in perceptual, neural, developmental, semiotic and social morphogenesis. The authors approach the ontogenetical issue by taking into account the morphogenetical process, involving the concept of individuation proposed by Gilbert Simondon and Gilles Deleuze. The target audience primarily comprises experts in the field but the book may also be beneficial for graduate students. The challenge of the genesis and constitution of "units" has (...) always been at the center of philosophical and scientific research. This ontogenetical issue is common to every discipline but it is articulated in different ways: in phenomenology of perception the constitution of perceptual units is at the base of gestalt field theories, in theoretical neuroscience synchronized neural assemblies are considered as correlates of conscious processes, in developmental embryogenesis the constitution of organs is the principle outcome of morphodynamic evolution while in social morphogenesis the constitution of coherent units is common to segmentary, gerarchic and functional differentiation. (shrink)

There are many morphologically distinct membrane structures with different functions at the surface of epithelial cells. Among these, adherens junctions (AJ) and tight junctions (TJ) are responsible for the mechanical linkage of epithelial cells and epithelial barrier function, respectively. In the process of new cell–cell adhesion formation between two epithelial cells, such as after wounding, AJ form first and then TJ form on the apical side of AJ. This process is very complicated because AJ formation triggers (...) drastic changes in the organization of actin cytoskeleton, the activity of Rho family of small GTPases, and the lipid composition of the plasma membrane, all of which are required for subsequent TJ formation. In this review, the authors focus on the relationship between AJ and TJ as a representative example of specialization of plasma membrane regions and introduce recent findings on how AJ formation promotes the subsequent formation of TJ. (shrink)

This article explores the ways new materialism centers the problem of morphogenesis—and de-centers language and culture—in philosophical accounts of corporeality. Attention to organic structures gives insight into the entanglement of nature and culture obscured by tendencies to think matter as lacking agential features. I suggest, in conclusion, that new materialism may operate with a notion of “entanglement” or “intra-activity” that is too productive. New materialisms may require a more pliable set of distinctions to capture the relations between morphogenetic forces.

Terminally differentiating stratified squamous epithelial cells assemble a specialized protective barrier structure on their periphery termed the cornified cell envelope (CE). It is composed of numerous structural proteins that become cross‐linked by several transglutaminase enzymes into an insoluble macromolecular assembly. Several proteins are involved in the initial stages of CE assembly, but only certain proteins from a choice of more than 20 different proteins are used in the final stages of CE reinforcement, apparently to meet tissue‐specific requirements. In addition, (...) a variable selection of proteins may be upregulated in response to genetic defects of one of the CE proteins or tissue injury, in an effort to maintain an effective barrier. Additionally, in the epidermis and hair fiber cuticle, a layer of lipids is covalently attached to the proteins, which provides essential water barrier properties. Here we describe our current understanding of CE structure, a possible mechanism of its assembly, and various disorders that cause a defective barrier. BioEssays 24:789–800, 2002. Published 2002 Wiley Periodicals, Inc. (shrink)

A geometrical model is proposed that describes the emergence of a primordium at the shoot apex in Dicotyledons. It is based on recent fundamental results on plant morphogenesis, viz.: – the emergence is preceded by the reorganization of the microtubules of the cortical cytoskeleton, leading to a new orientation of the synthesis of the cell wall microfibrils; – the resulting global stress is related to the general orientation of the cell growth.

Alan M. Turing’s last published work and some posthumously published manuscripts were dedicated to the development of his theory of organic pattern formation. In “The Chemical Basis of Morphogenesis” (1952), he provided an elaborated mathematical formulation of the theory of the origins of biological form that had been first proposed by Sir D’Arcy Wendworth Thompson in On Growth and Form (1917/1942). While arguably his most mathematically detailed and his systematically most ambitious effort, Turing’s morphogenetical writings also form the most (...) thematically self-contained and least philosophically explored part of his work. We dedicate our inquiry to the reasons and the implications of Turing’s choice of biological topic and viewpoint. We will probe for possible factors in Turing’s choice that go beyond availability and acquaintance with On Growth and Form. On these grounds, we will explore how and to what extent his theory of morphogenesis actually ties in with his concept of mechanistic computation. Notably, Thompson’s pioneering work in biological ‘structuralism’ was organicist in outlook and explicitly critical of the Darwinian approaches that were popular with Turing’s cyberneticist contemporaries—and partly used by Turing himself in his proto-connectionist models of learning. Resolving this apparent dichotomy, we demonstrate how Turing’s quest for mechanistic explanations of how organisation emerges in nature leaves room for a non-mechanist view of nature. (shrink)

New molecular markers for epidermal stem cells have enabled their isolation both in vitro and from the epidermis lying between hair follicles. Micro‐dissection experiments have localised a second population of stem cells within hair follicles. Epidermal stem cells have a patterned distribution in vivo. The patterning can be reconstituted in vitro, showing that it is generated by interactions between keratinocytes and that the differentiation of epidermal stem cells is regulated by signals from other keratinocytes. Recent evidence from transgenic mice suggests (...) that stem cell behaviour in the gut may be regulated by similar cell‐cell interactions in vivo. Candidate genes for mediating these interactions are the homologues of Drosophila cell fate patterning genes such as Notch and Wingless and the Cadherin family of cell‐cell adhesion molecules. The roles of stem cells and of mutations of the Patched gene in epithelial carcinogenesis are discussed. (shrink)

Patterns resulting from the sole interplay between reaction and diffusion are probably involved in certain stages of morphogenesis in biological systems, as initially proposed by Alan Turing. Self-organization phenomena of this type can only develop in nonlinear systems (i.e. involving positive and negative feedback loops) maintained far from equilibrium. We present Turing patterns experimentally observed in a chemical system. An oscillating chemical reaction, the CIMA reaction, is operated in an open spatial reactor designed in order to obtain a pure (...) reaction-diffusion system. The two types of Turing patterns observed, hexagonal arrays of spots and parallel stripes, are characterized by an intrinsic wavelength. We identify the origin of the necessary difference of diffusivity between activator and inhibitor. We also describe a pattern growth mechanism by spot splitting that recalls cell division. (shrink)

In 1952, Alan Turing published his last work on the concept of embryonic morphogenesis, propounding a computational framework for pattern formation within the developing embryo. This concept of morphogenesis and the concept of embryo pattern formation based on chemical diffusion patterns were corroborated with the discovery of the Homeobox or Hox genes. In the following decades, Hox gene research has expanded and is now shown to underlie the variety of morphological novelties that we experience in nature, the patterning (...) of structural aspects of different organs including the brain and also mutant animals that may in the future give rise to novel speciation. Turing had the foresight and vision and with his work created the field of computational biology and mathematical modeling in biological systems. In this paper, we will discuss the concept of Hox genes, their role in patterning the embryo, how it relates to Turing’s concept of morphogenesis and what further insights they may provide. (shrink)

Digital practices in design, together with computer-assisted manufacturing (CAM), have inspired the reflection of philosophers, theorists, and historians over the last decades. Gilles Deleuze’s The Fold: Leibniz and the Baroque (1988) presents one of the first and most successful concepts created to think about these new design and manufacturing practices.1 Deleuze proposed a new concept of the technological object, which was inspired by Bernard Cache’s digital design practices and computer-assisted manufacturing. Deleuze compared Cache’s practices to Leibniz’s differential calculus-based notion of (...) the parametric curve. From this perspective, the object is no longer an essential form: rather, it is functional, defined by a family of parametric curves. In Deleuze’s terms, it is an objectile. This definition grasps a particular aspect of modernity in the technological object, rendering possible the industrial production of “the unique object” (la pièce unique), while making obsolete the homogeneity that comes with industrial standardization. What follows introduces developmental biology into this design matrix, interrogating the relationship between parametric design and computer-assisted manufactory on the one hand and biological morphogenetic processes on the other. Is one necessary for the other? Does an architect need computation in order to render morphogenetic shapes? In answering these questions, this chapter displaces the centrality of digital technology in the design of shape-shifting forms within architecture and calls for a rethinking of design by way of analog prototypes. I argue that “thinking through analogs” offers another means of generating parametrically based morphogenetic forms. (shrink)

Margaret S. Archer is responsible for important conceptual developments in critical realism and the structure-agent problem but her explanatory framework often opposes those of other influential theorists. In this book she provides a response to critics of her work in the form of a set of discussions of published articles.

Working within an Archerian morphogenetic framework, I suggest that we need to pay more attention to practices. Instead of the mainstream focus on practice as action, I argue that we should pay attention to practices as a key structural and cultural element of analysis. Practices cannot be simply read-off from beliefs, that is, they are not an inevitable practical counterpart to belief. Although belief is relevant, it does not provide the full explanation for the presence of practices. Therefore, the same (...) or similar beliefs can result in significantly different practices depending on factors such as advances in technology and changes in modes of dissemination of theological doctrine. To illustrate my argument, I consider historical work on comparative religious practices, specifically the distinction between rituals and routines. A focus on the latter, as the conditions of possibility for the former, leads to some implications for the thesis of the morphogenesis of contemporary society. An analysis of the relationship between religious rituals and routines stresses the importance of placing both in their wider cultural and structural context. (shrink)

Shortly after implantation the embryonic lineage transforms from a coherent ball of cells into polarized cup shaped epithelium. Recently we elucidated a previously unknown apoptosis‐independent morphogenic event that reorganizes the pluripotent lineage. Polarization cues from the surrounding basement membrane rearrange the epiblast into a polarized rosette‐like structure, where subsequently a central lumen is established. Thus, we provided a new model revising the current concept of apoptosis‐dependent epiblast morphogenesis. Cell death however has to be tightly regulated during embryogenesis to ensure (...) developmental success. Here, we follow the stages of early mouse development and take a glimpse at the critical signaling and morphogenic events that determine cells destiny and reshape the embryonic lineage. (shrink)