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TGF-B Family Signaling in Epithelial Differentiation and Epithelial–Mesenchymal Transition

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TGF-B Family Signaling in Epithelial Differentiation and Epithelial–Mesenchymal Transition Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press TGF-b Family Signaling in Epithelial Differentiation and Epithelial–Mesenchymal Transition Kaoru Kahata,1 Mahsa Shahidi Dadras,1,2 and Aristidis Moustakas1,2 1Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, SE–751 24 Uppsala, Sweden 2Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, SE–751 23 Uppsala, Sweden Correspondence: [email protected] Epithelia exist in the animal body since the onset of embryonic development; they generate tissue barriers and specify organs and glands. Through epithelial–mesenchymal transitions (EMTs), epithelia generate mesenchymal cells that form new tissues and promote healing or disease manifestation when epithelial homeostasis is challenged physiologically or patho- logically. Transforming growth factor-bs (TGF-bs), activins, bone morphogenetic proteins (BMPs), and growth and differentiation factors (GDFs) have been implicated in the regulation of epithelial differentiation. These TGF-b family ligands are expressed and secreted at sites where the epithelium interacts with the mesenchyme and provide paracrine queues from the mesenchyme to the neighboring epithelium, helping the specification of differentiated ep- ithelial cell types within an organ. TGF-b ligands signal via Smads and cooperating kinase pathways and control the expression or activities of key transcription factors that promote either epithelial differentiation or mesenchymal transitions. In this review, we discuss evi- dence that illustrates how TGF-b family ligands contribute to epithelial differentiation and induce mesenchymal transitions, by focusing on the embryonic ectoderm and tissues that form the external mammalian body lining. TGF-b FAMILY MEMBERS IN EPITHELIAL activity and activate intracellular effectors such DIFFERENTIATION as Smad proteins and various signaling branch- es of protein kinases, lipid kinases, and small he transforming growth factor-b (TGF-b) GTPases (Hata and Chen 2016; Zhang 2017). Tfamily consists of secreted polypeptides The Smad branch of signaling mediators in- that include TGF-b1, TGF-b2, and TGF-b3, cludes receptor-activated Smads (R-Smads), activins, bone morphogenetic proteins (BMPs), a common mediator Smad (co-Smad), and and growth and differentiation factors (GDFs). inhibitory Smads (I-Smads). Five different R- These ligands signal after binding to type II Smads (Smad1, Smad2, Smad3, Smad5, and and type I receptors that show protein kinase Smad8) are directly phosphorylated by the Editors: Rik Derynck and Kohei Miyazono Additional Perspectives on The Biology of the TGF-b Family available at www.cshperspectives.org Copyright # 2018 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a022194 Cite this article as Cold Spring Harb Perspect Biol 2018;10:a022194 1 Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press K. Kahata et al. type I receptors. Phosphorylated R-Smads form enchymal cells. In addition to the mesenchymal heteromeric complexes with Smad4, the only inputs, epithelial cells are also capable of trans- mammalian co-Smad. Smad6 and Smad7 are differentiating to other cell types, through I-Smads, whose genes are transcriptionally in- processes that are collectively termed epithelial duced by the TGF-b, activin, and BMP path- plasticity. When the transdifferentiation gener- ways and limit the activities of these pathways ates mesenchymal cells, the process is best (Miyazawa and Miyazono 2016). The TGF-b known as epithelial–mesenchymal transition family is implicated in multiple stages of early (EMT) (Hay 1995; Lim and Thiery 2012). embryonic development; a prominent example EMT can be reversible and then leads to the is nodal, which signals the generation of prox- transdifferentiation from mesenchymal to epi- imodistal polarity in the early embryo (Schier thelial cells, known as mesenchymal–epithelial 2003; Robertson 2014). As embryonic morpho- transition (MET) (Nieto 2013). However, cases genesis proceeds, nodal also specifies endoder- of MET in which the starting cell source is a mal tissue differentiation, and controls the differentiated mesenchymal cell (e.g., a fibro- anteroposterior pattern of the embryo (Schier blast) have been reported mainly in the field 2003; Robertson 2014). In addition, left–right of induced pluripotent stem (iPS) cell technol- body asymmetry is regulated by nodal and ogy (Sanchez-Alvarado and Yamanaka 2014). BMPs (Shiratori and Hamada 2014). On the EMTand MET play critical roles in disease path- other hand, dorsoventral embryonic polarity is ogenesis (Kalluri and Weinberg 2009), such as controlled by BMP-specific extracellular antag- in cancer, in which TGF-b-induced EMT em- onists, such as chordin and noggin, which limit powers prometastatic potential, and in tissue the binding of BMPs to their signaling receptors fibrosis, in which BMP-induced MET counter- (Bierand De Robertis 2015). Thus, BMPs secret- acts fibrosis. In this review, we focus on roles of ed by dorsal embryonic tissue (i.e., the Spemann EMT and MET during normal development of organizer) repress gene expression, and BMPs epithelial organs. secreted by ventral tissue activate gene expres- Hallmarks of EMT are the remodeling of sion, generating a dorsoventral polar pattern of tight, adherens, and desmosomal junctions at differentiation in the emerging embryonic tis- the plasma membrane and remodeling of the sue (Bier and De Robertis 2015). Nodal and cytoskeleton, including actin microfilaments, BMPs and their extracellular antagonists, acting microtubules, and keratin or vimentin interme- in concentration-dependent gradients across diate filaments; these processes are driven by the early embryonic tissue, enable progenitor remodeling of polarity complexes in epithelial cells to generate the three embryonic line- cells (Wheelock et al. 2008; Nelson 2009; Huang ages—ectoderm, endoderm and mesoderm. et al. 2012). The TGF-b family plays prominent These three lineages subsequently generate di- roles in directing EMT and MET, and much is rectly or indirectly (i.e., through epithelial– already understood in relation to the signaling mesenchymal interactions) differentiated epi- pathways that mediate this epithelial response thelial cell types, which populate the various and the gene programs that control transdiffer- tissues discussed in this review. entiation (Lamouille et al. 2014). Historically, evidence that TGF-b members induce EMT was gathered in studies of heart EPITHELIAL–MESENCHYMAL AND valve formation; TGF-b2 transforms endothe- MESENCHYMAL–EPITHELIAL TRANSITIONS lial cells to mesenchymal cells that generate the IN EPITHELIAL ORGANOGENESIS cushions that line the septa in the heart valves Epithelial morphogenesis proceeds through (Mercado-Pimentel and Runyan 2007). This successive cycles of induction of epithelial pro- example expands the concept of EMT beyond liferation by the adjacent mesenchymal layer, epithelial cells and informs us that plasticity in followed by differentiation cycles, which are differentiation also takes place in the endothe- also positively or negatively controlled by mes- lium, thus named endothelial–mesenchymal 2 Cite this article as Cold Spring Harb Perspect Biol 2018;10:a022194 Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press TGF-b Family in Epithelial Differentiation transition (EndMT). Another critical observa- ing the other two layers (Robertson 2014). How- tion of EMT induced by TGF-b1 involved ever, gastrulation additionally encompasses mouse mammary epithelial NMuMG cells substantial epithelial cell invagination and (Miettinen et al. 1994). Subsequent research movement without EMT. defined molecular pathways and gene-based The epiblast EMT involves embryonic TGF- mechanisms that mediate the EMT program in b family ligands such as mouse nodal and NMuMG cells (Valcourt et al. 2005). In addi- chicken Vg1, or the mammalian Vg1 orthologs tion, TGF-b members drive EMT while arrest- GDF-1 and GDF-3 (Shah et al. 1997; Chea et al. ing the cell cycle of NMuMG cells (Gal et al. 2005; Andersson et al. 2007). Classical studies 2008). It is worth noting that epithelial cell cycle established that loss-of-function Nodal muta- arrest by TGF-bs, activins or BMPs is a hallmark tions in mice lead to defective gastrulation response that characterizes this family of cyto- (Robertson 2014). Moreover, transplantation kines (Massague´ 2012). It was also shown that experiments, aimed at rescuing the mutant BMPs, in a concentration-dependent manner, phenotype, showed that only very low doses of can overcome the positive effects of TGF-b in nodal protein, expressed by few cells, are suffi- driving EMT, thus promoting the epithelial cient and required to mediate the epiblast EMT phenotype (Kowanetz et al. 2004), which is rem- (Varlet et al. 1997). The binding of nodal to its iniscent of a positive effect of BMPs toward receptors is controlled by the extracellular in- MET (Zeisberg et al. 2003). However, it should hibitors lefty and cerberus-like, so that only cells be kept in mind that BMP signaling can also positioned at the correct place during tissue promote EMT in cancer (Davis et al. 2016) or ingression undergo EMT (Perea-Gomez et al. during neural crest delamination, as will be de- 2002; Bertocchini
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