BMP-2 induces cell migration and periostin expression during atrioventricular valvulogenesis.
Atrioventricular (AV) endocardium transforms into the cushion mesenchyme, the primordia of the valves and membranous septa, through epithelial-mesenchymal transformation (EMT). While bone morphogenetic protein (BMP)-2 is known to be critical for AV EMT, the role of BMP-2 in post-EMT AV valvulogenesis remains to be elucidated. To find BMP signaling loops, we first localized Type I BMP receptors (BMPRs), BMPR-1A (ALK3), -1B (ALK6) and ALK2 in AV cushion mesenchyme in stage-24 chick embryos. Based on the BMP receptor expression pattern, we examined the functional roles of BMP-2 and BMP signaling in post-EMT valvulogenesis by using stage-24 AV cushion mesenchymal cell aggregates cultured on 3D-collagen gels. Exogenous BMP-2 or constitutively active (ca) BMPR-1B (ALK6)-virus treatments induced migration of the mesenchymal cells into the collagen gels, whereas noggin, an antagonist of BMPs, or dominant-negative (dn) BMPR-1 B (ALK6)-virus treatments reduced cell migration from the mesenchymal cell aggregates. Exogenous BMP-2 or caBMPR-1B (ALK6) treatments significantly promoted expression of an extracellular matrix (ECM) protein, periostin, a known valvulogenic matrix maturation mediator, at both mRNA and protein levels, whereas periostin expression was repressed by adding noggin or dnBMPR-1B (ALK6)-virus to the culture. Moreover, transcripts of Twist and Id1, which have been implicated in cell migration in embryogenesis and activation of the periostin promoter, were induced by BMP-2 but repressed by noggin in cushion mesenchymal cell cultures. These data provide evidence that BMP-2 and BMP signaling induce biological processes involved in early AV valvulogenesis, i.e. mesenchymal cell migration and expression of periostin, indicating critical roles for BMP signaling in post-EMT AV cushion tissue maturation and differentiation.
Inai
Kei
K
Department of Cell Biology and Anatomy and Cardiovascular Developmental Biology Center, Medical University of South Carolina, 171 Ashley Ave., Charleston, SC 29425, USA.
Norris
Russell A
RA
Hoffman
Stanley
S
Markwald
Roger R
RR
Sugi
Yukiko
Y
D000818:Animals; D030161:Avian Proteins / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D055396:Bone Morphogenetic Protein 2; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002642:Chick Embryo; D017931:DNA Primers / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D054089:Endocardial Cushions / Q000166:cytology / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D017403:In Situ Hybridization; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology*; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism
D030161:Avian Proteins; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D015815:Cell Adhesion Molecules; D017931:DNA Primers; D051798:Inhibitor of Differentiation Protein 1; D012333:RNA, Messenger; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C412362:Twist protein, Gallus gallus; D051879:Twist-Related Protein 1; D052005:Bone Morphogenetic Protein Receptors, Type I