title: An exclusive cellular and molecular network governs intestinal smooth muscle cell differentiation in vertebrates.
abstract: Intestinal smooth muscle cells (iSMCs) are a crucial component of the adult gastrointestinal tract and support intestinal differentiation, peristalsis and epithelial homeostasis during development. Despite these crucial roles, the origin of iSMCs and the mechanisms responsible for their differentiation and function remain largely unknown in vertebrates. Here, we demonstrate that iSMCs arise from the lateral plate mesoderm (LPM) in a stepwise process. Combining pharmacological and genetic approaches, we show that TGFβ/Alk5 signaling drives the LPM ventral migration and commitment to an iSMC fate. The Alk5-dependent induction of zeb1a and foxo1a is required for this morphogenetic process: zeb1a is responsible for driving LPM migration around the gut, whereas foxo1a regulates LPM predisposition to iSMC differentiation. We further show that TGFβ, zeb1a and foxo1a are tightly linked together by miR-145 In iSMC-committed cells, TGFβ induces the expression of miR-145, which in turn is able to downregulate zeb1a and foxo1a The absence of miR-145 results in only a slight reduction in the number of iSMCs, which still express mesenchymal genes but fail to contract. Together, our data uncover a cascade of molecular events that govern distinct morphogenetic steps during the emergence and differentiation of vertebrate iSMCs.
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Turin 10126, Italy.
authors.forename: Dafne
authors.initials: D
authors.lastname: Gays
authors.affiliation: Institute of Molecular Life Sciences (IMLS), University of Zürich, Zürich 8057, Switzerland.
authors.forename: Christopher
authors.initials: C
authors.lastname: Hess
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Turin 10126, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Camporeale
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Turin 10126, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Ala
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Turin 10126, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Provero
authors.affiliation: Institute of Molecular Life Sciences (IMLS), University of Zürich, Zürich 8057, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Mosimann
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Turin 10126, Italy massimo.santoro@unito.it.|Vesalius Research Center, VIB-KUL, Leuven 3000, Belgium.
authors.forename: Massimo M
authors.identifier: 0000-0003-4605-5085
authors.initials: MM
authors.lastname: Santoro
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D000071161:Forkhead Box Protein O1 / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology* / Q000196:embryology; D008648:Mesoderm / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D008954:Models, Biological; D009024:Morphogenesis; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000071161:Forkhead Box Protein O1; D016212:Transforming Growth Factor beta; D029961:Zebrafish Proteins; D000071799:Zinc Finger E-box-Binding Homeobox 1; C576354:foxo1a protein, zebrafish; C583292:zeb1b protein, zebrafish
keywords: Lateral plate mesoderm; Organogenesis; Smooth muscle cells; Zebrafish