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Wnt/-Catenin Signaling in Tissue Self-Organization

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Wnt/-Catenin Signaling in Tissue Self-Organization G C A T T A C G G C A T genes Review Wnt/β-catenin Signaling in Tissue Self-Organization Kelvin W. Pond 1,*, Konstantin Doubrovinski 2 and Curtis A. Thorne 1 1 Department of Cellular and Molecular Medicine, The University of Arizona, Tucson, AZ 85719, USA; [email protected] 2 Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; [email protected] * Correspondence: [email protected] Received: 15 July 2020; Accepted: 11 August 2020; Published: 14 August 2020 Abstract: Across metazoans, animal body structures and tissues exist in robust patterns that arise seemingly out of stochasticity of a few early cells in the embryo. These patterns ensure proper tissue form and function during early embryogenesis, development, homeostasis, and regeneration. Fundamental questions are how these patterns are generated and maintained during tissue homeostasis and regeneration. Though fascinating scientists for generations, these ideas remain poorly understood. Today, it is apparent that the Wnt/β-catenin pathway plays a central role in tissue patterning. Wnt proteins are small diffusible morphogens which are essential for cell type specification and patterning of tissues. In this review, we highlight several mechanisms described where the spatial properties of Wnt/β-catenin signaling are controlled, allowing them to work in combination with other diffusible molecules to control tissue patterning. We discuss examples of this self-patterning behavior during development and adult tissues’ maintenance. The combination of new physiological culture systems, mathematical approaches, and synthetic biology will continue to fuel discoveries about how tissues are patterned. These insights are critical for understanding the intricate interplay of core patterning signals and how they become disrupted in disease. Keywords: Wnt; β-catenin; tissue patterning; tissue homeostasis; tissue organization; self-organization; reaction-diffusion; morphogens 1. The Wnt/β-catenin Pathway The Wnt pathway is a highly conserved cell-to-cell signaling pathway, appearing in metazoans from sponges [1] to nematodes [2] to chordates [3]. Wnt signaling plays essential roles in development, maintenance of tissue homeostasis, and regeneration of damaged tissue. After its role in Drosophila patterning and mouse tumor formation was discovered 40 years ago [4,5], Wnt has been extensively studied in virtually all model biological systems and continues to provide both basic biological insights and clues relevant to animal form, function, and disease. In this review, we will focus on the canonical Wnt/β-catenin pathway as a tissue organizing and self-organizing factor during embryogenesis/development and regeneration/homeostasis. For more general reviews on patterning and self-organization, the reader should also consider References [6–8]. β-catenin-independent Wnt pathways also exist, yet their activity has been less extensively studied in the context of tissue organization and patterning. For reviews on β-catenin-independent Wnt signaling, we refer the reader to References [9–12]. In the canonical Wnt/β-catenin pathway (Figure1), cells not receiving extracellular Wnt ligands maintain an active cytosolic destruction complex, which serves to degrade the continually expressed transcriptional co-activator β-catenin. The core components of the destruction complex consist of Axin, Adenomatous polyposis coli (APC), casein kinase 1 α (CK1α), glycogen synthase kinase 3 (GSK3), protein phosphatase 2A (PP2a), and the ubiquitin ligase βTrCP. Axin and APC bind β-catenin, which is Genes 2020, 11, 939; doi:10.3390/genes11080939 www.mdpi.com/journal/genes Genes 2020, 11, 939 2 of 18 Genes 2020, 11, x FOR PEER REVIEW 2 of 18 phosphorylated by CK1α and GSK3, exposing the βTrCP ubiquitin target site on β-catenin [13] and catenin, which is phosphorylated by CK1α and GSK3, exposing the βTrCP ubiquitin target site on β- leading to proteasomal degradation. This maintains low cytosolic levels of β-catenin in the absence of catenin [13] and leading to proteasomal degradation. This maintains low cytosolic levels of β-catenin a Wnt ligand. Upon binding of extracellular Wnt to the membrane receptors Frizzled and low-density in the absence of a Wnt ligand. Upon binding of extracellular Wnt to the membrane receptors Frizzled lipoprotein receptor-related protein 6 (Lrp6), Dishevelled is recruited and promotes inhibition and and low-density lipoprotein receptor-related protein 6 (Lrp6), Dishevelled is recruited and promotes possiblyinhibition disassembly and possibly of APC,disassembl Axin,y and of APC, GSK3. Axin, With and the GSK3. destruction With the complex destruction function complex suppressed, function β -cateninsuppressed, accumulates β-catenin and accumulates translocates and to translocates the nucleus to to the promote nucleus expression to promote of Wntexpression target genes.of Wnt β -catenintarget genes. target β-catenin genes are target transcribed genes are through transcribed cooperation through with cooperation several other with nuclearseveral other factors nuclear [14], includingfactors [14], the T-cellincluding factor the (TCF) T-cell transcription factor (TCF) factor, transcription which switches factor, roleswhich from switches a repressor roles from to an a activatorrepressor (reviewed to an activator in Reference (reviewed [15]). This in transcriptionReference [15]). program This initiatestranscription a downstream program cascade initiates of a eventsdownstream that can cascade drive proliferation, of events that di canfferentiation, drive prolif anderation, renewal differentiation, of the stem cellsand renewal [16], among of the other stem outcomescells [16], [17 among]. other outcomes [17]. FigureFigure 1. General1. General model model for the for Wnt the/β -cateninWnt/β-catenin signaling signaling pathway pathway and its regulation and its byregulation the destruction by the complex.destruction The destructioncomplex. The complex: destruction Axin, Adenomatouscomplex: Axin, polyposis Adenomatous coli (APC), polyposis casein kinase coli (APC), 1 α (CK1 caseinα), glycogenkinase 1 synthase α (CK1α kinase), glycogen 3 (GSK3), synthase protein kinase phosphatase 3 (GSK3), 2A protein (PP2a), phosphatase and the ubiquitin 2A (PP2a), ligase βandTrCP. the Membraneubiquitin receptors:ligase βTrCP. Frizzled Membrane (FZD) receptors: and low-density Frizzled lipoprotein (FZD) and receptor-related low-density lipoprotein protein 6 receptor- (Lrp6). Dishevelledrelated protein (Dvl) 6 T-cell (Lrp6). factor Dishevelled (TCF). (Dvl) T-cell factor (TCF). 2.2. Tissue Tissue Self-Organization Self-Organization TheThe ability ability of of a a single single cell cell to to give give rise rise to to the the complexity complexity of of a a multicellular multicellular organism organism has has fascinated fascinated scientistsscientists for for generations. generations. In In 1892, 1892, Hans Hans Dreisch Dreisch separated separated sea sea urchin urchin embryos embryos at at the the 4-cell 4-cell stage stage and and discovereddiscovered that that all all separated separated cells cells were were able able to to di differentiatefferentiate into into complete complete larvae larvae (Die (Die Biologie Biologie als als selbstständigeselbstständige Wissenschaft Wissenschaft (1893)). (1893)). This This raised raised the question,the question, what what keeps keeps the intact the 4-cellintact embryo4-cell embryo from givingfrom risegiving to fourrise to complete four complete larvae? larvae? Dreisch’s Dreisch’ discoverys discovery was critical was critical as it showed as it showed that a that cell’s a fatecell’s dependsfate depends on the externalon the external (in this case(in this inhibitory) case inhibi signalingtory) signaling from proximity from orproximity contact withor contact its neighbors. with its Thisneighbors. was also This a keystone was also discovery a keystone because discovery it showed because that early it showed cells are that autonomous early cells units are thatautonomous contain allunits the informationthat contain needed all the toinformation self-organize needed themselves to self-organize into complex themselves functional into tissues. complex functional tissues. Tissue self-organization is a key aspect of animal development and adult tissue homeostasis. We define self-organization as the process by which tissues can form patterns from an initial symmetrical Genes 2020, 11, 939 3 of 18 Tissue self-organization is a key aspect of animal development and adult tissue homeostasis. We define self-organization as the process by which tissues can form patterns from an initial symmetrical or chaotic state. Self-organization can be driven by diffusible molecules, cell–cell or cell–substrate signaling, and mechanical forces. These triggers allow cells to “sense” their neighbors and environment to adjust proliferation, growth, differentiation, death, etc., accordingly, to insure robust and uniform development, regeneration, and homeostasis. Cell adhesion-based signaling is also essential to tissue organization. For example, the mechanosensing transcription factor YAP is required for the initial symmetry breaking events seen in organoids [18] and crypt formation is also driven by the activity of integrins during gut development [19]. For excellent reviews on adhesion and tissue organization, we refer the reader to References [20–23]. Tissue self-organizing events can be separated into two categories: embryogenesis/body
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