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


Gays, Dafne; Hess, Christopher; Camporeale, Annalisa; Ala, Ugo; Provero, Paolo; Mosimann, Christian; Santoro, Massimo M (2017). An exclusive cellular and molecular network governs intestinal smooth muscle cell differentiation in vertebrates. Development, 144(3):464-478.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Institute of Molecular Life Sciences
Dewey Decimal Classification:570 Life sciences; biology
Uncontrolled Keywords:Developmental Biology, Molecular Biology
Language:English
Date:1 February 2017
Deposited On:19 Jan 2018 20:24
Last Modified:19 Aug 2018 13:03
Publisher:Company of Biologists
ISSN:0950-1991
Additional Information:http://dev.biologists.org/
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1242/dev.133926
PubMed ID:28049660
Project Information:
  • : FunderSNSF
  • : Grant IDPP00P3_139093
  • : Project TitleDeciphering the control of lateral mesoderm cell fates in zebrafish

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