title: Fkbp1a controls ventricular myocardium trabeculation and compaction by regulating endocardial Notch1 activity.
abstract: Trabeculation and compaction of the embryonic myocardium are morphogenetic events crucial for the formation and function of the ventricular walls. Fkbp1a (FKBP12) is a ubiquitously expressed cis-trans peptidyl-prolyl isomerase. Fkbp1a-deficient mice develop ventricular hypertrabeculation and noncompaction. To determine the physiological function of Fkbp1a in regulating the intercellular and intracellular signaling pathways involved in ventricular trabeculation and compaction, we generated a series of Fkbp1a conditional knockouts. Surprisingly, cardiomyocyte-restricted ablation of Fkbp1a did not give rise to the ventricular developmental defect, whereas endothelial cell-restricted ablation of Fkbp1a recapitulated the ventricular hypertrabeculation and noncompaction observed in Fkbp1a systemically deficient mice, suggesting an important contribution of Fkbp1a within the developing endocardia in regulating the morphogenesis of ventricular trabeculation and compaction. Further analysis demonstrated that Fkbp1a is a novel negative modulator of activated Notch1. Activated Notch1 (N1ICD) was significantly upregulated in Fkbp1a-ablated endothelial cells in vivo and in vitro. Overexpression of Fkbp1a significantly reduced the stability of N1ICD and direct inhibition of Notch signaling significantly reduced hypertrabeculation in Fkbp1a-deficient mice. Our findings suggest that Fkbp1a-mediated regulation of Notch1 plays an important role in intercellular communication between endocardium and myocardium, which is crucial in controlling the formation of the ventricular walls.
authors.affiliation: Riley Heart Research Center, Division of Pediatric Cardiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. hanchen@iu.edu
authors.forename: Hanying
authors.initials: H
authors.lastname: Chen
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhang
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Sun
authors.forename: Momoko
authors.initials: M
authors.lastname: Yoshimoto
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Chen
authors.forename: Wuqiang
authors.initials: W
authors.lastname: Zhu
authors.forename: Jijia
authors.initials: J
authors.lastname: Liu
authors.forename: Yadan
authors.initials: Y
authors.lastname: Shen
authors.forename: Weidong
authors.initials: W
authors.lastname: Yong
authors.forename: Deqiang
authors.initials: D
authors.lastname: Li
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Lin
authors.forename: Baiyan
authors.initials: B
authors.lastname: Li
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: VanDusen
authors.forename: Paige
authors.initials: P
authors.lastname: Snider
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schwartz
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Conway
authors.forename: Loren J
authors.initials: LJ
authors.lastname: Field
authors.forename: Mervin C
authors.initials: MC
authors.lastname: Yoder
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Firulli
authors.forename: Nadia
authors.initials: N
authors.lastname: Carlesso
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Towbin
authors.forename: Weinian
authors.initials: W
authors.lastname: Shou
mesh_terms: D000818:Animals; D019070:Cell Lineage; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D047108:Embryonic Development; D004699:Endocardium / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006352:Heart Ventricles / Q000196:embryology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000196:embryology / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009432:Neural Crest / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D022021:Tacrolimus Binding Proteins