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

Development. 2017 Feb 1;144(3):464-478. doi: 10.1242/dev.133926. Epub 2017 Jan 3.


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.

Keywords: 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
  • Intestinal Mucosa / metabolism
  • Intestines / cytology*
  • Intestines / embryology
  • 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


  • Forkhead Box Protein O1
  • Transforming Growth Factor beta
  • Zebrafish Proteins
  • Zinc Finger E-box-Binding Homeobox 1
  • foxo1a protein, zebrafish
  • zeb1b protein, zebrafish