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A critical developmental role for tgfbr2 in myogenic cell lineages is revealed in mice expressing SM22-Cre, not SMMHC-Cre

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Author

  • Andrew D. Frutkin
  • Haikun Shi
  • Goro Otsuka
  • Per Levéen
  • Stefan Karlsson
  • David A. Dichek

Summary, in English

Smooth muscle cell (SMC)-specific deletion of transforming growth factor beta (TGF-beta) signaling would help elucidate the mechanisms through which TGF-beta signaling contributes to vascular development and disease. We attempted to generate mice with SMC-specific deletion of TGF-beta signaling by mating mice with a conditional ("floxed") allele for the type 11 TGF-beta receptor (tgfbr2(flox)) to mice with SMC-targeted expression of Cre recombinase. We bred male mice transgenic for smooth muscle myosin heavy chain (SMMHC)-Cre with females carrying tgfbr2(flox). Surprisingly, SMMHC-Cre rnice recombined tglbr2(flox) at low levels in SMC and at high levels in the testis. Recombination of tgfbr2(flox) in testis correlated with high-level expression of SMMHC-Cre in testis and germline transmission of tgfbr2(null). In contrast, mice expressing Cre from a SM22 alpha promoter (SM22-Cre) efficiently recombined tgfbr2(flox) in vascular and visceral SMC and the heart, but not in testis. Use of the R26R reporter allele confirmed that Cre-mediated recombination in vascular SMC was inefficient for SMMHC-Cre mice and highly efficient for SM22-Cre mice. Breedings that introduced the SM22-Cre allele into tgfbr2(flox) zygotes in order to generate adult mice that are hemizygous for SM22-Cre and homozygous for tgfbr2(flox) and would have conversion of tgfbr2(flox/flox) to tgfbr2(null/null) in SMC-produced no live SM22-Cre : tgfbr2(flox/flox) pups (P < 0.001). We conclude: (1) "SMC-targeted" Cre lines vary significantly in specificity and efficiency of Cre expression; (2) TGF-beta signaling in the subset of cells that express SM22 alpha is required for normal development; (3) generation of adult mice with absent TGF-beta signaling in SMC remains a challenge. (c) 2006 Elsevier Inc. All rights reserved.

Publishing year

2006

Language

English

Pages

724-731

Publication/Series

Journal of Molecular and Cellular Cardiology

Volume

41

Issue

4

Document type

Journal article

Publisher

Elsevier

Topic

  • Cardiac and Cardiovascular Systems

Keywords

  • SM22 alpha
  • smooth
  • Cre recombinase
  • smooth muscle cells
  • type II TGF-beta receptor
  • muscle myosin heavy chain

Status

Published

ISBN/ISSN/Other

  • ISSN: 1095-8584