Smooth and cardiac muscle-selective knock-out of Krüppel-like factor 4 causes postnatal death and growth retardation

Tadashi Yoshida, Qiong Gan, Aaron S. Franke, Ruoya Ho, Jifeng Zhang, Y. Eugene Chen, Matsuhiko Hayashi, Mark W. Majesky, Avril V. Somlyo, Gary K. Owens

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Abstract

Krüppel-like factor 4 (Klf4) is a transcription factor involved in differentiation and proliferation in multiple tissues.We demonstrated previously that tamoxifen-induced deletion of the Klf4 gene in mice accelerated neointimal formation but delayed down-regulation of smooth muscle cell differentiation markers in carotid arteries following injury. To further determine the role of Klf4 in the cardiovascular system, we herein derived mice deficient for the Klf4 gene in smooth and cardiac muscle using the SM22α promoter (SM22α-CreKI+/Klf4loxP/loxP mice). SM22α-CreKI+/Klf4loxP/loxP mice were born at the expected Mendelian ratio, but they gradually died after birth. Although ∼40% of SM22α-CreKI+/Klf4loxP/loxP mice survived beyond postnatal day 28, they exhibited marked growth retardation. In wild-type mice, Klf4 was expressed in the heart from late embryonic development through adulthood, whereas it was not expressed in smooth muscle. No changes were observed in morphology or expression of smooth muscle cell differentiation markers in vessels of SM22α-CreKI+/Klf4loxP/loxP mice. Of interest, cardiac output was significantly decreased in SM22α-CreKI+/Klf4loxP/loxP mice, as determined by magnetic resonance imaging. Moreover, a lack of Klf4 in the heart resulted in the reduction in expression of multiple cardiac genes, including Gata4. In vivo chromatin immunoprecipitation assays on the heart revealed that Klf4 bound to the promoter region of the Gata4 gene. Results provide novel evidence that Klf4 plays a key role in late fetal and/or postnatal cardiac development.

Original languageEnglish
Pages (from-to)21175-21184
Number of pages10
JournalJournal of Biological Chemistry
Volume285
Issue number27
DOIs
Publication statusPublished - 2010 Jul 2

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Yoshida, T., Gan, Q., Franke, A. S., Ho, R., Zhang, J., Chen, Y. E., Hayashi, M., Majesky, M. W., Somlyo, A. V., & Owens, G. K. (2010). Smooth and cardiac muscle-selective knock-out of Krüppel-like factor 4 causes postnatal death and growth retardation. Journal of Biological Chemistry, 285(27), 21175-21184. https://doi.org/10.1074/jbc.M110.112482