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WIREs Dev Biol
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Of plasticity and specificity: dialectics of the microenvironment and macroenvironment and the organ phenotype

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The study of biological form and how it arises is the domain of the developmental biologists; but once the form is achieved, the organ poses a fascinating conundrum for all the life scientists: how are form and function maintained in adult organs throughout most of the life of the organism? That they do appears to contradict the inherently plastic nature of organogenesis during development. How do cells with the same genetic information arrive at, and maintain such different architectures and functions, and how do they keep remembering that they are different from each other? It is now clear that narratives based solely on genes and an irreversible regulatory dynamics cannot answer these questions satisfactorily, and the concept of microenvironmental signaling needs to be added to the equation. During development, cells rearrange and differentiate in response to diffusive morphogens, juxtacrine signals, and the extracellular matrix (ECM). These components, which constitute the modular microenvironment, are sensitive to cues from other tissues and organs of the developing embryo as well as from the external macroenvironment. On the other hand, once the organ is formed, these modular constituents integrate and constrain the organ architecture, which ensures structural and functional homeostasis and therefore, organ specificity. We argue here that a corollary of the above is that once the organ architecture is compromised in adults by mutations or by changes in the microenvironment such as aging or inflammation, that organ becomes subjected to the developmental and embryonic circuits in search of a new identity. But since the microenvironment is no longer embryonic, the confusion leads to cancer: hence as we have argued, tumors become new evolutionary organs perhaps in search of an elusive homeostasis. WIREs Dev Biol 2014, 3:147–163. doi: 10.1002/wdev.130

Conflict of interest: The authors have declared no conflicts of interest for this article.

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Patterning functions of morphogens and extracellular matrix ECM in mammary gland morphogenesis. Upper panel: Confocal image of an engineered Y‐shaped mammary epithelial branching tubule with (a) cells stained for actin (red), and nuclei (green). The computed spatial map of inhibitory diffusible morphogen TGF‐β, produced by mammary epithelial cells (and shown in the form of a heatmap in (b)) predicts that the local concentration of the inhibitor is highest at the point of trifurcation (where initiation of branching does not take place) and lowest at the distal ends of the tubules, where branching is allowed (c). Branching is determined by the interplay of the local tissue geometry and the spatial geometry of morphogen diffusion. (Reprinted with permission from Ref . Copyright 2006 Nature Publishing Group). Lower panel: Mouse mammary epithelial cells when cultured on top of laminin‐111‐rich ECM, develop into spheroid multicellular structures that are encased in basement membrane. These structures resemble in vivo mammary acini in size and shape. After 4 days, a lumen forms through epithelial cell death in the center. The lumen then fills up with milk, secreted by the peripheral epithelial cells. The lower left panel is a light microscope picture of an acinus from a section of a gland in vivo. The lower middle panel shows a low magnification transmission electron microscopic image of an acinus formed in culture. (Reprinted with permission from Ref . Copyright 1989 The Company of Biologists).
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Organ specificity in three dimensions (3D): an emergent property of a multicomponent interaction network. Systems biology potentially reveals the relationship between homeostasis and cancer. Shown here is an n‐dimensional interaction space with the axes representing protein expression levels. State I depicts the phenotypic organization of normal/nonmalignant mammary gland as an acinus that emerges if the mammary epithelial cells are placed in laminin‐rich ECM (lrECM). The acinus is characterized by cellular quiescence, basal and apical polarity and lumen formation. An intact laminin‐111‐rich basement membrane (BM) ensures repression of oncogenic signaling pathways and downregulation of a metalloproteinase MMP9. State II depicts an amorphous phenotype with loss in acinar organization and polarity and cell proliferation, all of which occur when proteolytic MMPs are overexpressed in either nonmalignant human breast cells (MMP9) or in mammary glands in vivo (MMP3). Overexpression of MMP results in proteolysis and destruction of the BM, leading to loss in tissue specificity and eventually tumors. State III depicts a reverted and reorganized mammary epithelial phenotype with growth arrest, a partial restoration of polarity (only basal polarity returns). The reversion occurs when one or more of the oncogenic signaling pathways or MMPs are inhibited.
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Coherent morphomechanics of cells in organ specificity and embryogenesis. (a) Coherent angular motion (CAMo) of nonmalignant S1 breast epithelial cells occurs when they are cultured in three dimensional (3D) gels leading to the formation of polar spheroidal acinar‐like structures as revealed by live imaging of the cells with fluorescent signals from the nuclear histone (green) and actin cytoskeleton (red) (upper and middle panels). By day 5, the S1 acini growth arrest (lowermost panel) with concurrent lumen formation. (Reprinted with permission from Ref . Copyright 2012 National Academy of Sciences, USA). (b) Synchronized circumferential rotation of Drosophila follicular cells coincides with axis elongation of its eggs. The left and middle figures of upper panel show follicular elongation as Drosophila oogenesis proceeds. Upper right figure shows quantification of the aspect ratio of the elongating follicle. Lower panel shows the synchronized revolution of follicular cells (through yellow and white dots and arrows) and their germline nuclei (red, blue asterisks and arrow) against collagen IV (green) containing microenvironment as oogenesis takes place (Reprinted with permission from Ref . Copyright 2011 American Association for the Advancement of Science).
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