Mammary Morphogenesis

Developmental Cell Article Mammary Morphogenesis and Regeneration Require the Inhibition of EMT at Terminal End Buds by Ovol2 Transcriptional Repressor Kazuhide Watanabe, 1 Alvaro V illarreal-Ponce, 1 Peng Sun, 1 Michael L. Salmans, 1 Magid Fallahi, 1 Bogi Andersen, 1,2 and Xing Dai 1, * 1 Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA 2 Department of Medicine, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA *Correspondence: [email protected] http://dx.d oi.org/10.1016/j.de vcel.2014.03.006 SUMMARY Epithelial cells possess remarkable plasticity, having the abi lit y to become mesenchymal cells thr ough alt erations in adh esio n and mot ili ty (epithelial- to- mesenchymal tr ansi ti on [EMT] ). However, how epith elial plastic ity is kept in check in epithe lial cells dur ing tissue dev elopmen t and rege nera tion re- mains to be ful ly understood. Here we show that restricting the EMT of mammary epithelial cells by tr anscri pt ion fac tor Ovol 2 is require d for pr oper morpho genesis and regene ration. Deletion of Ovol2 blocks mammary ducta l morphoge nesis, depletes stem and pr ogenit or cell reser voir s, and leads epithelial cells to undergo EMT in vivo to become non epit helial cell types. Ovol2 dir ectl y represses myr iad EMT induce rs, and its abse nce switches response to TGF -b fr om growth ar rest to EMT. Furthermore, forced expression of the repressor iso- form of Ovol2 is able to reprogram metastatic breast cancer cel ls from a mesenchymal to an epi thelial state. Our ﬁndings underscore the cri tical impor- tance of exquis itely regulating epithelia l plast icity in devel opment and cancer. INTRODUCTION The induction of pluripotency in terminally differentiated cell types ( Takahashi and Yamanaka, 2006 ) and the existence of pluripotent cells in physiological adult tissues ( Roy et al., 2013 ) highl ight the remar kabl e linea ge plas ticit y of soma tic cell s. Although this plasticity offers immense opportunities for regen- erative medicine,it rai sesquest ion s as to howto properlyrestri ct plasticity during the dynamic processes of tissue development and reg ene rat ion . Cel ls of epi the lial lineages can und erg o pheno typic changes to gain mese nchymal fea tures throu gh an epithelial-to-mesenchymal transition (EMT) program ( Kalluri and Weinberg, 2009 ). Complete EMT occurs during mesoderm or neural crest formation to generate fully committed mesen- chy mal cell typ es ( Thi ery et al. , 2009 ), whereas partial and reversible EMT occurs during morphogenesis of certain epithelial tissues such as mammary gland (MG) ( Nakaya and Sheng, 2013 ). Although much has been learned about the molecular mechanisms that promote EMT during early development and in cancer cells, genetic pathways that regulate partial EMT during tissu e morphogen esis to maint ain epit helia l lineages are poorly characterized . MG undergoes dramatic tissue growth and remodeling during puberty and pregnancy, generating not only luminal epithelial cells but also a unique mesenchymal-like epithelial population, namely, basal/myoepithelial cells ( Watson and Khaled, 2008 ). Thus, MG serves as an ideal system to study the genetic circuits that control epithelial lineage plasticity. At puberty, mammary epi the lial ste m/prog enitor cells that reside in the ter min al end buds (TEBs) undergo collective migration to drive ductal morphogenesis ( Ewald et al., 2008 ). This process involves the acquisition of motility while preserving overall epithelial integrity. Moreover, a partial loss and reestablishment of epithelial adhe- sion and polarity occur at the TEBs ( Ewald et al., 2008, 2012; Kouros-Mehr and Werb, 2006; Nanba et al., 2001 ). These ﬁnd- ings imply that both epithelial plasticity-promoting and -restricting mec han isms might be imp ort ant for the mor pho genic potential of TEB stem/ prog enitor cell s( Godde et al., 201 0 ). Preg- nancy induces dramatic expansion and regression of epithelial components as well as dynamic remodeling of the stromal envi- ronment ( Watson and Khaled, 2008 ), creating yet another developmental window where epithelial lineage plasticity may have to be intricately regulated. The basal/myoepithelial population of adult MG cont ains the so-c alle d multip otent mammary stem cells (MaSCs) that, upon trans plant atio n, are capa ble of rege ner- ating an entire epithelial network composed of both luminal and basal/myo epit helia l linea ges ( Sha ckl eto n et al. , 2006; Sti ngl et al., 2006 ). Adult stem cells with bipotential or unipotential have also been found in the mammary basal compartment via linea ge traci ng under physi olog ical cond itions ( Ri os et al., 2014; Van Keyme ulen et al., 2011 ). Recent, largely in vitro, studies have implicated several EMT-inducing transcription fac- tors (EMT-TFs), such as Snail, Slug, and Zeb1, as important fac- tors that promote stemness in normal and malignant mammary epithelial cells (MECs) ( Chaffer et al., 2013; Guo et al., 2012; Mani et al., 2008; Nassour et al., 2012 ). However, the in vivo mecha nisms that restr ict epit helia l linea ge plast icity to safe guard diffe renti atio n and how such mechanis ms regul ate stem cell function durin g MG morph ogen esis and rege neration remain poorly understood. Developmental Cell 29, 59–74, April 14, 2014 ª2014 Elsevier Inc. 59

Mammary Morphogenesis

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