An exclusive cellular and molecular network governs intestinal smooth muscle cell differentiation in vertebrates

Gays, D., Hess, C., Camporeale, A., Ala, U., Provero, P., Mosimann, C., Santoro, M.M.
Development (Cambridge, England)   144(3): 464-478 (Journal)
Registered Authors
Gays, Dafne, Hess, Christopher, Mosimann, Christian, Santoro, Massimo
lateral plate mesoderm, organogenesis, smooth muscle cells, zebrafish
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Cell Differentiation/genetics
  • Cell Differentiation/physiology
  • Forkhead Box Protein O1/genetics
  • Forkhead Box Protein O1/metabolism
  • Gene Expression Regulation, Developmental
  • Gene Knockdown Techniques
  • Intestines/cytology*
  • Intestines/embryology
  • Intestines/metabolism
  • Mesoderm/cytology
  • Mesoderm/embryology
  • Mesoderm/metabolism
  • Models, Biological
  • Morphogenesis
  • Myocytes, Smooth Muscle/cytology*
  • Myocytes, Smooth Muscle/metabolism
  • Promoter Regions, Genetic
  • Signal Transduction
  • Transforming Growth Factor beta/metabolism
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
  • Zinc Finger E-box-Binding Homeobox 1/genetics
  • Zinc Finger E-box-Binding Homeobox 1/metabolism
28049660 Full text @ Development
Intestinal smooth muscle cells (iSMCs) are a critical component of the adult gastrointestinal (GI) tract and support intestinal differentiation, peristalsis, and epithelial homeostasis during development. Despite these critical roles, the origin of iSMCs and the mechanisms responsible for their differentiation and function remain fairly unknown in vertebrates. Here, using genetic lineage tracing in zebrafish, we demonstrated that iSMCs arise from the lateral plate mesoderm (LPM) in a stepwise process. Early during organogenesis, LPM cells progressively migrate ventral to the endoderm tube wrapping the developing gut. Concomitantly, the LPM differentiates by turning on early SMC markers. Combining pharmacological and genetic approaches, we show that TGF-β/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 to drive LPM migration around the gut, while foxo1a regulates LPM predisposition to iSMC differentiation. We further show that the three factors TGF-β, zeb1a, and foxo1a are tightly linked together by miR-145 In iSMC-committed cells, TGF-β induces the expression of miR-145 that in turn is able to downregulate zeb1a and foxo1a The absence of miR-145 results in only a slight reduction of iSMCs, which however still express mesenchymal genes yet 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.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes