Fkbp1a controls ventricular myocardium trabeculation and compaction by regulating endocardial Notch1 activity

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. FirulliNadia Carlesso, Jeffrey A. Towbin, Weinian Shou

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1946-1957
Number of pages12
JournalDevelopment (Cambridge)
Volume140
Issue number9
DOIs
StatePublished - May 1 2013

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Myocardium
Endothelial Cells
Tacrolimus Binding Protein 1A
Peptidylprolyl Isomerase
Endocardium
Ventricular Function
Morphogenesis
Cardiac Myocytes
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Developmental Biology

Cite this

Fkbp1a controls ventricular myocardium trabeculation and compaction by regulating endocardial Notch1 activity. / Chen, Hanying; Zhang, Wenjun; Sun, Xiaoxin; Yoshimoto, Momoko; Chen, Zhuang; Zhu, Wuqiang; Liu, Jijia; Shen, Yadan; Yong, Weidong; Li, Deqiang; Zhang, Jin; Lin, Yang; Li, Baiyan; VanDusen, Nathan J.; Snider, Paige; Schwartz, Robert J.; Conway, Simon J.; Field, Loren J.; Yoder, Mervin C.; Firulli, Anthony B.; Carlesso, Nadia; Towbin, Jeffrey A.; Shou, Weinian.

In: Development (Cambridge), Vol. 140, No. 9, 01.05.2013, p. 1946-1957.

Research output: Contribution to journalArticle

Chen, H, Zhang, W, Sun, X, Yoshimoto, M, Chen, Z, Zhu, W, Liu, J, Shen, Y, Yong, W, Li, D, Zhang, J, Lin, Y, Li, B, VanDusen, NJ, Snider, P, Schwartz, RJ, Conway, SJ, Field, LJ, Yoder, MC, Firulli, AB, Carlesso, N, Towbin, JA & Shou, W 2013, 'Fkbp1a controls ventricular myocardium trabeculation and compaction by regulating endocardial Notch1 activity', Development (Cambridge), vol. 140, no. 9, pp. 1946-1957. https://doi.org/10.1242/dev.089920
Chen, Hanying ; Zhang, Wenjun ; Sun, Xiaoxin ; Yoshimoto, Momoko ; Chen, Zhuang ; Zhu, Wuqiang ; Liu, Jijia ; Shen, Yadan ; Yong, Weidong ; Li, Deqiang ; Zhang, Jin ; Lin, Yang ; Li, Baiyan ; VanDusen, Nathan J. ; Snider, Paige ; Schwartz, Robert J. ; Conway, Simon J. ; Field, Loren J. ; Yoder, Mervin C. ; Firulli, Anthony B. ; Carlesso, Nadia ; Towbin, Jeffrey A. ; Shou, Weinian. / Fkbp1a controls ventricular myocardium trabeculation and compaction by regulating endocardial Notch1 activity. In: Development (Cambridge). 2013 ; Vol. 140, No. 9. pp. 1946-1957.
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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.",
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AU - Zhu, Wuqiang

AU - Liu, Jijia

AU - Shen, Yadan

AU - Yong, Weidong

AU - Li, Deqiang

AU - Zhang, Jin

AU - Lin, Yang

AU - Li, Baiyan

AU - VanDusen, Nathan J.

AU - Snider, Paige

AU - Schwartz, Robert J.

AU - Conway, Simon J.

AU - Field, Loren J.

AU - Yoder, Mervin C.

AU - Firulli, Anthony B.

AU - Carlesso, Nadia

AU - Towbin, Jeffrey A.

AU - Shou, Weinian

PY - 2013/5/1

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N2 - 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.

AB - 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.

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