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

Dev Biol. 1998 Jul 1;199(1):72-9. doi: 10.1006/dbio.1998.8905.

Abstract

TGF beta family members are implicated in cardiac organogenesis, growth control, and positional information, including the direction of cardiac looping. However, genetic analysis of TGF beta signaling in mice has been confounded, in some cases, by noncardiac and generalized defects. Hence, deciphering TGF beta function in myocardium would benefit from cardiac-restricted mutations. We developed a constitutively activated type I receptor, ALK5L193A,P194A,T204D, and directed it to embryonic myocardium in transgenic mice. Expression of the activated ALK5 gene arrests looping 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 looping, perhaps through control of cardiac myocyte proliferation.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Activin Receptors, Type I*
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Differentiation
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / biosynthesis
  • DNA-Binding Proteins
  • Heart / embryology*
  • Homeobox Protein Nkx-2.5
  • Homeodomain Proteins
  • Mice
  • Mice, Mutant Strains
  • Morphogenesis
  • Mutation*
  • Myocardium / cytology
  • Protein Serine-Threonine Kinases / genetics*
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / genetics*
  • Signal Transduction
  • Transcription Factors
  • Xenopus Proteins*
  • Zebrafish Proteins

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • DNA-Binding Proteins
  • Hand2 protein, mouse
  • Homeobox Protein Nkx-2.5
  • Homeodomain Proteins
  • NKX2-5 protein, human
  • Nkx2-5 protein, mouse
  • Receptors, Transforming Growth Factor beta
  • Transcription Factors
  • Xenopus Proteins
  • Zebrafish Proteins
  • hand2 protein, zebrafish
  • Protein Serine-Threonine Kinases
  • Activin Receptors, Type I
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human
  • Tgfbr1 protein, mouse