Hedgehog signaling controls homeostasis of adult intestinal smooth muscle

William J. Zacharias, Blair B. Madison, Katherine E. Kretovich, Katherine D. Walton, Neil Richards, Aaron M. Udager, Xing Li, Deborah L. Gumucio

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

The Hedgehog (Hh) pathway plays multiple patterning roles during development of the mammalian gastrointestinal tract, but its role in adult gut function has not been extensively examined. Here we show that chronic reduction in the combined epithelial Indian (Ihh) and Sonic (Shh) hedgehog signal leads to mislocalization of intestinal subepithelial myofibroblasts, loss of smooth muscle in villus cores and muscularis mucosa as well as crypt hyperplasia. In contrast, chronic over-expression of Ihh in the intestinal epithelium leads to progressive expansion of villus smooth muscle, but does not result in reduced epithelial proliferation. Together, these mouse models show that smooth muscle populations in the adult intestinal lamina propria are highly sensitive to the level of Hh ligand. We demonstrate further that Hh ligand drives smooth muscle differentiation in primary intestinal mesenchyme cultures and that cell-autonomous Hh signal transduction in C3H10T1/2 cells activates the smooth muscle master regulator Myocardin (Myocd) and induces smooth muscle differentiation. The rapid kinetics of Myocd activation by Hh ligands as well as the presence of an unusual concentration of Gli sties in this gene suggest that regulation of Myocd by Hh might be direct. Thus, these data indicate that Hh is a critical regulator of adult intestinal smooth muscle homeostasis and suggest an important link between Hh signaling and Myocd activation. Moreover, the data support the idea that lowered Hh signals promote crypt expansion and increased epithelial cell proliferation, but indicate that chronically increased Hh ligand levels do not dampen crypt proliferation as previously proposed.

Original languageEnglish (US)
Pages (from-to)152-162
Number of pages11
JournalDevelopmental Biology
Volume355
Issue number1
DOIs
StatePublished - Jan 1 2011
Externally publishedYes

Fingerprint

Hedgehogs
Smooth Muscle
Homeostasis
Ligands
Hordeolum
Mucous Membrane
Myofibroblasts
Mesoderm
Intestinal Mucosa
Smooth Muscle Myocytes
Hyperplasia
Gastrointestinal Tract
Signal Transduction
Cell Culture Techniques
Epithelial Cells
Cell Proliferation

Keywords

  • Crypt proliferation
  • Epithelial/mesenchymal interactions
  • Hedgehog
  • Inflammatory bowel disease
  • Intestinal visceral myopathy
  • Myocardin
  • Villus smooth muscle

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

Zacharias, W. J., Madison, B. B., Kretovich, K. E., Walton, K. D., Richards, N., Udager, A. M., ... Gumucio, D. L. (2011). Hedgehog signaling controls homeostasis of adult intestinal smooth muscle. Developmental Biology, 355(1), 152-162. https://doi.org/10.1016/j.ydbio.2011.04.025

Hedgehog signaling controls homeostasis of adult intestinal smooth muscle. / Zacharias, William J.; Madison, Blair B.; Kretovich, Katherine E.; Walton, Katherine D.; Richards, Neil; Udager, Aaron M.; Li, Xing; Gumucio, Deborah L.

In: Developmental Biology, Vol. 355, No. 1, 01.01.2011, p. 152-162.

Research output: Contribution to journalArticle

Zacharias, WJ, Madison, BB, Kretovich, KE, Walton, KD, Richards, N, Udager, AM, Li, X & Gumucio, DL 2011, 'Hedgehog signaling controls homeostasis of adult intestinal smooth muscle', Developmental Biology, vol. 355, no. 1, pp. 152-162. https://doi.org/10.1016/j.ydbio.2011.04.025
Zacharias WJ, Madison BB, Kretovich KE, Walton KD, Richards N, Udager AM et al. Hedgehog signaling controls homeostasis of adult intestinal smooth muscle. Developmental Biology. 2011 Jan 1;355(1):152-162. https://doi.org/10.1016/j.ydbio.2011.04.025
Zacharias, William J. ; Madison, Blair B. ; Kretovich, Katherine E. ; Walton, Katherine D. ; Richards, Neil ; Udager, Aaron M. ; Li, Xing ; Gumucio, Deborah L. / Hedgehog signaling controls homeostasis of adult intestinal smooth muscle. In: Developmental Biology. 2011 ; Vol. 355, No. 1. pp. 152-162.
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