Document Detail


Fkbp1a controls ventricular myocardium trabeculation and compaction by regulating endocardial Notch1 activity.
MedLine Citation:
PMID:  23571217     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Hanying Chen; Wenjun Zhang; Xiaoxin Sun; Momoko Yoshimoto; Zhuang Chen; Wuqiang Zhu; Jijia Liu; Yadan Shen; Weidong Yong; Deqiang Li; Jin Zhang; Yang Lin; Baiyan Li; Nathan J VanDusen; Paige Snider; Robert J Schwartz; Simon J Conway; Loren J Field; Mervin C Yoder; Anthony B Firulli; Nadia Carlesso; Jeffrey A Towbin; Weinian Shou
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Development (Cambridge, England)     Volume:  140     ISSN:  1477-9129     ISO Abbreviation:  Development     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-10     Completed Date:  2013-05-31     Revised Date:  2014-05-07    
Medline Journal Info:
Nlm Unique ID:  8701744     Medline TA:  Development     Country:  England    
Other Details:
Languages:  eng     Pagination:  1946-57     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Lineage
Cells, Cultured
Embryo, Mammalian / embryology,  metabolism,  pathology
Embryonic Development
Endocardium / embryology,  metabolism*,  pathology
Endothelial Cells / metabolism,  pathology
Female
Gene Expression Regulation, Developmental
HEK293 Cells
Heart Ventricles / embryology,  metabolism,  pathology*
Humans
Immunohistochemistry
Male
Mice
Mice, Knockout / embryology,  metabolism
Myocardium / metabolism*,  pathology
Neural Crest / metabolism,  pathology
Phenotype
Receptor, Notch1 / genetics,  metabolism*
Signal Transduction
Tacrolimus Binding Proteins / genetics,  metabolism*
Transfection
Grant Support
ID/Acronym/Agency:
HL81092/HL/NHLBI NIH HHS; HL85098/HL/NHLBI NIH HHS; R01 AR061392/AR/NIAMS NIH HHS; R01 HL081092/HL/NHLBI NIH HHS; R01 HL109205/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Notch1 protein, mouse; 0/Receptor, Notch1; EC 5.2.1.-/Tacrolimus Binding Proteins
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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