The role of cell autonomous signaling by BMP in endocardial cushion cells in AV valvuloseptal morphogenesis

Yukiko Sugi, Bin Zhou, Kei Inai, Yuji Mishina, Jessica L. Burnside

Research output: Chapter in Book/Report/Conference proceedingChapter

1 Citation (Scopus)

Abstract

Distal outgrowth and fusion of the mesenchymalized AV endocardial cushions are essential morphogenetic events in AV valvuloseptal morphogenesis. BMP-2 myocardial conditional knockout (cKO) mice die early by embryonic day (ED) 10.5 [1], hampering investigation of the role of BMP-2 in AV valvuloseptal morphogenesis after this stage. In our previous study, we localized BMP-2 and type I BMP receptors, BMPR1A and Alk2, in AV endocardial cushions [2, 3]. Based on their expression patterns, we hypothesize that autocrine signaling by BMP-2 within mesenchymalized AV cushions plays a critical role during AV valvuloseptal morphogenesis. To test this hypothesis, we employed recently generated endocardial/endocardial cushion-specific cre-driver line Nfact1 Cre. Unlike a previously generated Nfatc1 enCre line whose cre-mediated recombination is restricted to AV and OT endocardium, this Nfatc1 Cre line confers cre-mediated recombination within the endocardial cells as well as their mesenchymal progeny. Using the Nfactc1 Cre driver line, we disrupted BMPR1A (Alk3) and BMP-2 specifically from AV endocardium and endocardial cushions. BMPR1A endocardial cushion cKO (cKO Endo) mouse embryos died by ED 12.5 and exhibited failure of cellularization of AV cushions (Fig. 22.1a-c) and disruption of extracellular matrix (ECM) protein deposition in the cushion mesenchyme. On the other hand, AV cushion formation occurred in the BMP-2 cKO Endo mice that survived beyond the AV cushion formation stage because BMP-2 expression remained intact in the AV myocardium during AV cushion formation. BMP-2 cKO Endo mice exhibited perimembranous ventricular septal defects (VSDs) (Fig. 22.1d, e), defective deposition of ECMs in the membranous septum, and AV mitral valve dysplasia, suggesting the cell autonomous requirement of BMP-2 in AV endocardial cushions. BMP-2 cKO Endo did not exhibit muscular VSDs. These data strongly support our hypothesis that cell autonomous signaling by BMP-2 in the endocardial lineage plays a significant role in mesenchymalized AV cushions during AV valvuloseptal morphogenesis.

Original languageEnglish (US)
Title of host publicationEtiology and Morphogenesis of Congenital Heart Disease: From Gene Function and Cellular Interaction to Morphology
PublisherSpringer Japan
Pages171-173
Number of pages3
ISBN (Electronic)9784431546283
ISBN (Print)9784431546276
DOIs
StatePublished - Jan 1 2016

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Endocardial Cushions
Morphogenesis
Type I Bone Morphogenetic Protein Receptors
Military electronic countermeasures
Knockout Mice
Defects
Extracellular Matrix Proteins
Endocardium
Fusion reactions
Ventricular Heart Septal Defects
Genetic Recombination
Autocrine Communication
Mesoderm
Mitral Valve
Myocardium
Embryonic Structures

Keywords

  • Atrioventricular (AV) canal
  • BMP receptors
  • BMP-2
  • Endocardial cushion
  • Valvuloseptal morphogenesis

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Sugi, Y., Zhou, B., Inai, K., Mishina, Y., & Burnside, J. L. (2016). The role of cell autonomous signaling by BMP in endocardial cushion cells in AV valvuloseptal morphogenesis. In Etiology and Morphogenesis of Congenital Heart Disease: From Gene Function and Cellular Interaction to Morphology (pp. 171-173). Springer Japan. https://doi.org/10.1007/978-4-431-54628-3_22

The role of cell autonomous signaling by BMP in endocardial cushion cells in AV valvuloseptal morphogenesis. / Sugi, Yukiko; Zhou, Bin; Inai, Kei; Mishina, Yuji; Burnside, Jessica L.

Etiology and Morphogenesis of Congenital Heart Disease: From Gene Function and Cellular Interaction to Morphology. Springer Japan, 2016. p. 171-173.

Research output: Chapter in Book/Report/Conference proceedingChapter

Sugi, Y, Zhou, B, Inai, K, Mishina, Y & Burnside, JL 2016, The role of cell autonomous signaling by BMP in endocardial cushion cells in AV valvuloseptal morphogenesis. in Etiology and Morphogenesis of Congenital Heart Disease: From Gene Function and Cellular Interaction to Morphology. Springer Japan, pp. 171-173. https://doi.org/10.1007/978-4-431-54628-3_22
Sugi Y, Zhou B, Inai K, Mishina Y, Burnside JL. The role of cell autonomous signaling by BMP in endocardial cushion cells in AV valvuloseptal morphogenesis. In Etiology and Morphogenesis of Congenital Heart Disease: From Gene Function and Cellular Interaction to Morphology. Springer Japan. 2016. p. 171-173 https://doi.org/10.1007/978-4-431-54628-3_22
Sugi, Yukiko ; Zhou, Bin ; Inai, Kei ; Mishina, Yuji ; Burnside, Jessica L. / The role of cell autonomous signaling by BMP in endocardial cushion cells in AV valvuloseptal morphogenesis. Etiology and Morphogenesis of Congenital Heart Disease: From Gene Function and Cellular Interaction to Morphology. Springer Japan, 2016. pp. 171-173
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