Pharyngeal Mesoderm Regulatory Network Controls Cardiac and Head Muscle Morphogenesis

Proc Natl Acad Sci U S A. 2012 Nov 13;109(46):18839-44. doi: 10.1073/pnas.1208690109. Epub 2012 Oct 29.

Abstract

The search for developmental mechanisms driving vertebrate organogenesis has paved the way toward a deeper understanding of birth defects. During embryogenesis, parts of the heart and craniofacial muscles arise from pharyngeal mesoderm (PM) progenitors. Here, we reveal a hierarchical regulatory network of a set of transcription factors expressed in the PM that initiates heart and craniofacial organogenesis. Genetic perturbation of this network in mice resulted in heart and craniofacial muscle defects, revealing robust cross-regulation between its members. We identified Lhx2 as a previously undescribed player during cardiac and pharyngeal muscle development. Lhx2 and Tcf21 genetically interact with Tbx1, the major determinant in the etiology of DiGeorge/velo-cardio-facial/22q11.2 deletion syndrome. Furthermore, knockout of these genes in the mouse recapitulates specific cardiac features of this syndrome. We suggest that PM-derived cardiogenesis and myogenesis are network properties rather than properties specific to individual PM members. These findings shed new light on the developmental underpinnings of congenital defects.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Body Patterning / physiology*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Embryo, Mammalian / embryology*
  • Head / embryology*
  • Heart / embryology*
  • Intracellular Signaling Peptides and Proteins
  • Mesoderm / embryology*
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / embryology*
  • Myocardium*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Lnx2 protein, mouse
  • Tcf21 protein, mouse