Inhibition of Notch2 by Numb/Numblike controls myocardial compaction in the heart

Cardiovasc Res. 2012 Nov 1;96(2):276-85. doi: 10.1093/cvr/cvs250. Epub 2012 Aug 3.

Abstract

Aims: The ventricular wall of the heart is composed of trabeculated and compact layers, which are separated by yet unknown processes during embryonic development. Here, we wanted to explore the role of Notch2 and Numb/Numblike for myocardial trabeculation and compaction.

Methods and results: We found that Notch2 activity is specifically down-regulated in the compact layer during cardiac development in the mouse. The biological role of Notch2 down-regulation was investigated by the expression of constitutively active Notch2 in the myocardium of transgenic mice, resulting in hypertrabeculation, reduced compaction, and ventricular septum defects. To disclose the mechanism that inhibited Notch2 activity during the formation of myocardial layers, we analysed potential suppressors of Notch signalling. We unveiled that concomitant but not separate ablation of Numb and Numblike in the developing heart leads to increased Notch2 activity along with hypertrabeculation, reduced compaction, and ventricular septum defects, phenocopying effects gained by overexpression of constitutively active Notch2. Expression profiling revealed a strong up-regulation of Bmp10 in Numb/Numblike mutant hearts, which might also interfere with trabeculation and compaction.

Conclusion: This study identified potential novel roles of Numb/Numblike in regulating trabeculation and compaction by inhibiting Notch2 and Bmp10 signalling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Proteins / metabolism
  • Embryo, Mammalian / metabolism
  • Embryo, Nonmammalian / metabolism
  • Female
  • Gene Knockdown Techniques
  • Genes, Reporter
  • Heart / embryology*
  • Homeobox Protein Nkx-2.5
  • Homeodomain Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Myocardium / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Pregnancy
  • Receptor, Notch2 / metabolism*
  • Transcription Factors / metabolism
  • Up-Regulation
  • Zebrafish

Substances

  • Bmp10 protein, mouse
  • Bone Morphogenetic Proteins
  • Homeobox Protein Nkx-2.5
  • Homeodomain Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Nkx2-5 protein, mouse
  • Notch2 protein, mouse
  • Numb protein, mouse
  • Numbl protein, mouse
  • Receptor, Notch2
  • Transcription Factors