A constitutive mutation of ALK5 disrupts cardiac looping and morphogenesis in mice

Min Ji Charng, Peter A. Frenkel, Qing Lin, Miho Yumada, Robert J. Schwartz, Eric N. Olson, Paul Overbeek, Michael D. Schneider

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

TGFβ family members are implicated in cardiac organogenesis, growth control, and positional information, including the direction of cardiac 1ooping. However, genetic analysis of TGFβ signaling in mice has been confounded, in some cases, by noncardiac and generalized defects. Hence, deciphering TGFβ function in myocardium would benefit from cardiacrestricted mutations. We developed a constitutively activated type I receptor, ALK5(L193A, P194A, T204D), and directed it to embryonic myocardium in transgenic mice. Expression of the activated ALK5 gene arrests 1ooping morphogenesis and causes a linear, dilated, hypoplastic heart tube, despite normal expression of Nkx2.5 and dHAND, cardiogenic transcription factors whose absence provokes a similar phenotype. Ventricular hypoplasia was associated with precocious induction of the cyclin-dependent kinase inhibitor, p21. Thus, an ALK5-sensitive pathway mediates 1ooping, perhaps through control of cardiac myocyte proliferation.

Original languageEnglish (US)
Pages (from-to)72-79
Number of pages8
JournalDevelopmental Biology
Volume199
Issue number1
DOIs
StatePublished - Jul 1 1998

Fingerprint

Morphogenesis
Myocardium
Cyclin-Dependent Kinase Inhibitor p21
Mutation
Organogenesis
Cardiac Myocytes
Transgenic Mice
Transcription Factors
Phenotype
Growth
Genes
Direction compound

Keywords

  • ALK5
  • Cardiac development
  • Looping
  • P21
  • TGFβ

ASJC Scopus subject areas

  • Developmental Biology

Cite this

Charng, M. J., Frenkel, P. A., Lin, Q., Yumada, M., Schwartz, R. J., Olson, E. N., ... Schneider, M. D. (1998). A constitutive mutation of ALK5 disrupts cardiac looping and morphogenesis in mice. Developmental Biology, 199(1), 72-79. https://doi.org/10.1006/dbio.1998.8905

A constitutive mutation of ALK5 disrupts cardiac looping and morphogenesis in mice. / Charng, Min Ji; Frenkel, Peter A.; Lin, Qing; Yumada, Miho; Schwartz, Robert J.; Olson, Eric N.; Overbeek, Paul; Schneider, Michael D.

In: Developmental Biology, Vol. 199, No. 1, 01.07.1998, p. 72-79.

Research output: Contribution to journalArticle

Charng, MJ, Frenkel, PA, Lin, Q, Yumada, M, Schwartz, RJ, Olson, EN, Overbeek, P & Schneider, MD 1998, 'A constitutive mutation of ALK5 disrupts cardiac looping and morphogenesis in mice', Developmental Biology, vol. 199, no. 1, pp. 72-79. https://doi.org/10.1006/dbio.1998.8905
Charng, Min Ji ; Frenkel, Peter A. ; Lin, Qing ; Yumada, Miho ; Schwartz, Robert J. ; Olson, Eric N. ; Overbeek, Paul ; Schneider, Michael D. / A constitutive mutation of ALK5 disrupts cardiac looping and morphogenesis in mice. In: Developmental Biology. 1998 ; Vol. 199, No. 1. pp. 72-79.
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