title: Inhibition of Notch2 by Numb/Numblike controls myocardial compaction in the heart.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  This study identified potential novel roles of Numb/Numblike in regulating trabeculation and compaction by inhibiting Notch2 and Bmp10 signalling.
authors.affiliation: Department of Cardiac Development and Remodelling,  Max-Planck-Institute for Heart and Lung Research, Ludwigstr. 43, Bad Nauheim 61231,  Germany.
authors.forename: Jiwen
authors.initials: J
authors.lastname: Yang
authors.forename: Sandra
authors.initials: S
authors.lastname: Bücker
authors.forename: Benno
authors.initials: B
authors.lastname: Jungblut
authors.forename: Thomas
authors.initials: T
authors.lastname: Böttger
authors.forename: Yuval
authors.initials: Y
authors.lastname: Cinnamon
authors.forename: Jan
authors.initials: J
authors.lastname: Tchorz
authors.forename: Matthias
authors.initials: M
authors.lastname: Müller
authors.forename: Bernhard
authors.initials: B
authors.lastname: Bettler
authors.forename: Richard
authors.initials: R
authors.lastname: Harvey
authors.forename: Qing-Yuan
authors.initials: QY
authors.lastname: Sun
authors.forename: Andre
authors.initials: A
authors.lastname: Schneider
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D017930:Genes, Reporter; D006321:Heart / Q000196:embryology*; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D051883:Receptor, Notch2 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation; D015027:Zebrafish
chemical_list: C119152:Bmp10 protein, mouse; D019485:Bone Morphogenetic Proteins; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C484469:Nkx2-5 protein, mouse; C497765:Notch2 protein, mouse; C106293:Numb protein, mouse; C106292:Numbl protein, mouse; D051883:Receptor, Notch2; D014157:Transcription Factors