Spatial-temporal targeting of lung-specific mesenchyme by a Tbx4 enhancer

Wenming Zhang, Douglas B. Menke, Meisheng Jiang, Hui Chen, David Warburton, Gianluca Turcatel, Chi Han Lu, Wei Xu, Yongfeng Luo, Wei Shi

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Background: Reciprocal interactions between lung mesenchymal and epithelial cells play essential roles in lung organogenesis and homeostasis. Although the molecular markers and related animal models that target lung epithelial cells are relatively well studied, molecular markers of lung mesenchymal cells and the genetic tools to target and/or manipulate gene expression in a lung mesenchyme-specific manner are not available, which becomes a critical barrier to the study of lung mesenchymal biology and the related pulmonary diseases. Results: We have identified a mouse Tbx4 gene enhancer that contains conserved DNA sequences across many vertebrate species with lung or lung-like gas exchange organ. We then generate a mouse line to express rtTA/LacZ under the control of the Tbx4 lung enhancer, and therefore a Tet-On inducible transgenic system to target lung mesenchymal cells at different developmental stages. By combining a Tbx4-rtTA driven Tet-On inducible Cre expression mouse line with a Cre reporter mouse line, the spatial-temporal patterns of Tbx4 lung enhancer targeted lung mesenchymal cells were defined. Pulmonary endothelial cells and vascular smooth muscle cells were targeted by the Tbx4-rtTA driver line prior to E11.5 and E15.5, respectively, while other subtypes of lung mesenchymal cells including airway smooth muscle cells, fibroblasts, pericytes could be targeted during the entire developmental stage. Conclusions: Developmental lung mesenchymal cells can be specifically marked by Tbx4 lung enhancer activity. With our newly created Tbx4 lung enhancer-driven Tet-On inducible system, lung mesenchymal cells can be specifically and differentially targeted in vivo for the first time by controlling the doxycycline induction time window. This novel system provides a unique tool to study lung mesenchymal cell lineages and gene functions in lung mesenchymal development, injury repair, and regeneration in mice.

Original languageEnglish (US)
Article number111
JournalBMC Biology
Volume11
DOIs
StatePublished - Nov 13 2013

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Mesoderm
developmental stage
targeting
Muscle
muscle
Genes
lungs
Cells
Lung
Pulmonary diseases
gene
Doxycycline
DNA sequences
Endothelial cells
homeostasis
Fibroblasts
gas exchange
Gene expression
repair
gene expression

Keywords

  • Lung mesenchyme
  • Tbx4 lung enhancer
  • Tet-On system

ASJC Scopus subject areas

  • Biotechnology
  • Structural Biology
  • Ecology, Evolution, Behavior and Systematics
  • Physiology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Plant Science
  • Developmental Biology
  • Cell Biology

Cite this

Zhang, W., Menke, D. B., Jiang, M., Chen, H., Warburton, D., Turcatel, G., ... Shi, W. (2013). Spatial-temporal targeting of lung-specific mesenchyme by a Tbx4 enhancer. BMC Biology, 11, [111]. https://doi.org/10.1186/1741-7007-11-111

Spatial-temporal targeting of lung-specific mesenchyme by a Tbx4 enhancer. / Zhang, Wenming; Menke, Douglas B.; Jiang, Meisheng; Chen, Hui; Warburton, David; Turcatel, Gianluca; Lu, Chi Han; Xu, Wei; Luo, Yongfeng; Shi, Wei.

In: BMC Biology, Vol. 11, 111, 13.11.2013.

Research output: Contribution to journalArticle

Zhang, W, Menke, DB, Jiang, M, Chen, H, Warburton, D, Turcatel, G, Lu, CH, Xu, W, Luo, Y & Shi, W 2013, 'Spatial-temporal targeting of lung-specific mesenchyme by a Tbx4 enhancer', BMC Biology, vol. 11, 111. https://doi.org/10.1186/1741-7007-11-111
Zhang W, Menke DB, Jiang M, Chen H, Warburton D, Turcatel G et al. Spatial-temporal targeting of lung-specific mesenchyme by a Tbx4 enhancer. BMC Biology. 2013 Nov 13;11. 111. https://doi.org/10.1186/1741-7007-11-111
Zhang, Wenming ; Menke, Douglas B. ; Jiang, Meisheng ; Chen, Hui ; Warburton, David ; Turcatel, Gianluca ; Lu, Chi Han ; Xu, Wei ; Luo, Yongfeng ; Shi, Wei. / Spatial-temporal targeting of lung-specific mesenchyme by a Tbx4 enhancer. In: BMC Biology. 2013 ; Vol. 11.
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abstract = "Background: Reciprocal interactions between lung mesenchymal and epithelial cells play essential roles in lung organogenesis and homeostasis. Although the molecular markers and related animal models that target lung epithelial cells are relatively well studied, molecular markers of lung mesenchymal cells and the genetic tools to target and/or manipulate gene expression in a lung mesenchyme-specific manner are not available, which becomes a critical barrier to the study of lung mesenchymal biology and the related pulmonary diseases. Results: We have identified a mouse Tbx4 gene enhancer that contains conserved DNA sequences across many vertebrate species with lung or lung-like gas exchange organ. We then generate a mouse line to express rtTA/LacZ under the control of the Tbx4 lung enhancer, and therefore a Tet-On inducible transgenic system to target lung mesenchymal cells at different developmental stages. By combining a Tbx4-rtTA driven Tet-On inducible Cre expression mouse line with a Cre reporter mouse line, the spatial-temporal patterns of Tbx4 lung enhancer targeted lung mesenchymal cells were defined. Pulmonary endothelial cells and vascular smooth muscle cells were targeted by the Tbx4-rtTA driver line prior to E11.5 and E15.5, respectively, while other subtypes of lung mesenchymal cells including airway smooth muscle cells, fibroblasts, pericytes could be targeted during the entire developmental stage. Conclusions: Developmental lung mesenchymal cells can be specifically marked by Tbx4 lung enhancer activity. With our newly created Tbx4 lung enhancer-driven Tet-On inducible system, lung mesenchymal cells can be specifically and differentially targeted in vivo for the first time by controlling the doxycycline induction time window. This novel system provides a unique tool to study lung mesenchymal cell lineages and gene functions in lung mesenchymal development, injury repair, and regeneration in mice.",
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