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

Frutkin, Andrew D. ; Shi, Haikun ; Otsuka, Goro ; Levéen, Per LU ; Karlsson, Stefan LU orcid and Dichek, David A. (2006) In Journal of Molecular and Cellular Cardiology 41(4). p.724-731
Abstract
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... (More)
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. (Less)
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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
SM22 alpha, smooth, Cre recombinase, smooth muscle cells, type II TGF-beta receptor, muscle myosin heavy chain
in
Journal of Molecular and Cellular Cardiology
volume
41
issue
4
pages
724 - 731
publisher
Elsevier
external identifiers
  • wos:000241403900018
  • scopus:33748542875
  • pmid:16887142
ISSN
1095-8584
DOI
10.1016/j.yjmcc.2006.06.067
language
English
LU publication?
yes
id
e169c8e8-31c9-493a-b0df-4609e8680d30 (old id 386704)
date added to LUP
2016-04-01 16:06:34
date last changed
2021-09-22 03:56:15
@article{e169c8e8-31c9-493a-b0df-4609e8680d30,
  abstract     = {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 &lt; 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.},
  author       = {Frutkin, Andrew D. and Shi, Haikun and Otsuka, Goro and Levéen, Per and Karlsson, Stefan and Dichek, David A.},
  issn         = {1095-8584},
  language     = {eng},
  number       = {4},
  pages        = {724--731},
  publisher    = {Elsevier},
  series       = {Journal of Molecular and Cellular Cardiology},
  title        = {A critical developmental role for tgfbr2 in myogenic cell lineages is revealed in mice expressing SM22-Cre, not SMMHC-Cre},
  url          = {http://dx.doi.org/10.1016/j.yjmcc.2006.06.067},
  doi          = {10.1016/j.yjmcc.2006.06.067},
  volume       = {41},
  year         = {2006},
}