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Leptin affects endocardial cushion formation by modulating EMT and migration via Akt signaling cascades.

Nath AK, Brown RM, Michaud M, Sierra-Honigmann MR, Snyder M, Madri JA - J. Cell Biol. (2008)

Bottom Line: Blood circulation is dependent on heart valves to direct blood flow through the heart and great vessels.Abnormal EMT and remodeling contribute to the etiology of several congenital heart defects.Our data suggest that an Akt signaling pathway underlies the observed phenotype.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, School of Medicine, Yale University, New Haven, CT 06510, USA.

ABSTRACT
Blood circulation is dependent on heart valves to direct blood flow through the heart and great vessels. Valve development relies on epithelial to mesenchymal transition (EMT), a central feature of embryonic development and metastatic cancer. Abnormal EMT and remodeling contribute to the etiology of several congenital heart defects. Leptin and its receptor were detected in the mouse embryonic heart. Using an ex vivo model of cardiac EMT, the inhibition of leptin results in a signal transducer and activator of transcription 3 and Snail/vascular endothelial cadherin-independent decrease in EMT and migration. Our data suggest that an Akt signaling pathway underlies the observed phenotype. Furthermore, loss of leptin phenocopied the functional inhibition of alphavbeta3 integrin receptor and resulted in decreased alphavbeta3 integrin and matrix metalloprotease 2, suggesting that the leptin signaling pathway is involved in adhesion and migration processes. This study adds leptin to the repertoire of factors that mediate EMT and, for the first time, demonstrates a role for the interleukin 6 family in embryonic EMT.

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Spatiotemporal localization of leptin during endocardial cushion morphogenesis. Immunofluorescence staining (red) for leptin was performed on embryonic hearts excised at E8.5 (A), E9.0 (B), E9.5 (C), E10.5 (D), E11.5 (E), and E12.5 (F). DAPI, blue. Myo, myocardium; En, endocardium; Mes, mesenchyme; CJ, cardiac jelly. Insets are enlargements of the endothelium overlaying the endocardial cushion (A), the myocardium adjacent to the endocardial cushion (B), and the mesenchymal cells within the endocardial cushion (E).
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fig1: Spatiotemporal localization of leptin during endocardial cushion morphogenesis. Immunofluorescence staining (red) for leptin was performed on embryonic hearts excised at E8.5 (A), E9.0 (B), E9.5 (C), E10.5 (D), E11.5 (E), and E12.5 (F). DAPI, blue. Myo, myocardium; En, endocardium; Mes, mesenchyme; CJ, cardiac jelly. Insets are enlargements of the endothelium overlaying the endocardial cushion (A), the myocardium adjacent to the endocardial cushion (B), and the mesenchymal cells within the endocardial cushion (E).

Mentions: A series of immunofluorescence images from embryonic day (E) 8.5–12.5 hearts, representing stages through the formation of endocardial cushion protrusions to the remodeling of endocardial mesenchyme, was captured to evaluate leptin distribution during valvulogenesis. At E8.5, as the myocardium secretes matrix molecules, swelling the extracellular space between the myocardial and endocardial layers, leptin presence is strong in the myocardium throughout the heart, including the trabeculating myocardium in the common ventricle (Fig. 1 A). The endocardium over the endocardial cushions and throughout the heart possesses a weakly detectable level of leptin (Fig. 1 A, inset). Induction of EMT begins shortly after formation of the acellular endocardial cushions. As the first few cells delaminate from the endocardial layer (E9.0), the punctuate pattern of leptin decreases in the myocardium (Fig. 1 B, inset), but expression begins to appear in the newly formed mesenchymal cells (Fig. 1 C). At the later stages of endocardial cushion morphogenesis (E9.5–12.5), myocardial expression continues to abate; however, expression in the endocardium and mesenchymal cells increases during stages of active EMT (Fig. 1, C and D), proliferation (Fig. 1 E), and early remodeling (Fig. 1 F), displaying an increasingly filamentous pattern (Fig. 1 E, inset). The dynamic expression of leptin throughout endocardial cushion morphogenesis suggests regulatory roles in early EMT events such as myocardial induction of EMT and maintenance of EMT as well as in later migratory roles in the remodeling cushion.


Leptin affects endocardial cushion formation by modulating EMT and migration via Akt signaling cascades.

Nath AK, Brown RM, Michaud M, Sierra-Honigmann MR, Snyder M, Madri JA - J. Cell Biol. (2008)

Spatiotemporal localization of leptin during endocardial cushion morphogenesis. Immunofluorescence staining (red) for leptin was performed on embryonic hearts excised at E8.5 (A), E9.0 (B), E9.5 (C), E10.5 (D), E11.5 (E), and E12.5 (F). DAPI, blue. Myo, myocardium; En, endocardium; Mes, mesenchyme; CJ, cardiac jelly. Insets are enlargements of the endothelium overlaying the endocardial cushion (A), the myocardium adjacent to the endocardial cushion (B), and the mesenchymal cells within the endocardial cushion (E).
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Related In: Results  -  Collection

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fig1: Spatiotemporal localization of leptin during endocardial cushion morphogenesis. Immunofluorescence staining (red) for leptin was performed on embryonic hearts excised at E8.5 (A), E9.0 (B), E9.5 (C), E10.5 (D), E11.5 (E), and E12.5 (F). DAPI, blue. Myo, myocardium; En, endocardium; Mes, mesenchyme; CJ, cardiac jelly. Insets are enlargements of the endothelium overlaying the endocardial cushion (A), the myocardium adjacent to the endocardial cushion (B), and the mesenchymal cells within the endocardial cushion (E).
Mentions: A series of immunofluorescence images from embryonic day (E) 8.5–12.5 hearts, representing stages through the formation of endocardial cushion protrusions to the remodeling of endocardial mesenchyme, was captured to evaluate leptin distribution during valvulogenesis. At E8.5, as the myocardium secretes matrix molecules, swelling the extracellular space between the myocardial and endocardial layers, leptin presence is strong in the myocardium throughout the heart, including the trabeculating myocardium in the common ventricle (Fig. 1 A). The endocardium over the endocardial cushions and throughout the heart possesses a weakly detectable level of leptin (Fig. 1 A, inset). Induction of EMT begins shortly after formation of the acellular endocardial cushions. As the first few cells delaminate from the endocardial layer (E9.0), the punctuate pattern of leptin decreases in the myocardium (Fig. 1 B, inset), but expression begins to appear in the newly formed mesenchymal cells (Fig. 1 C). At the later stages of endocardial cushion morphogenesis (E9.5–12.5), myocardial expression continues to abate; however, expression in the endocardium and mesenchymal cells increases during stages of active EMT (Fig. 1, C and D), proliferation (Fig. 1 E), and early remodeling (Fig. 1 F), displaying an increasingly filamentous pattern (Fig. 1 E, inset). The dynamic expression of leptin throughout endocardial cushion morphogenesis suggests regulatory roles in early EMT events such as myocardial induction of EMT and maintenance of EMT as well as in later migratory roles in the remodeling cushion.

Bottom Line: Blood circulation is dependent on heart valves to direct blood flow through the heart and great vessels.Abnormal EMT and remodeling contribute to the etiology of several congenital heart defects.Our data suggest that an Akt signaling pathway underlies the observed phenotype.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, School of Medicine, Yale University, New Haven, CT 06510, USA.

ABSTRACT
Blood circulation is dependent on heart valves to direct blood flow through the heart and great vessels. Valve development relies on epithelial to mesenchymal transition (EMT), a central feature of embryonic development and metastatic cancer. Abnormal EMT and remodeling contribute to the etiology of several congenital heart defects. Leptin and its receptor were detected in the mouse embryonic heart. Using an ex vivo model of cardiac EMT, the inhibition of leptin results in a signal transducer and activator of transcription 3 and Snail/vascular endothelial cadherin-independent decrease in EMT and migration. Our data suggest that an Akt signaling pathway underlies the observed phenotype. Furthermore, loss of leptin phenocopied the functional inhibition of alphavbeta3 integrin receptor and resulted in decreased alphavbeta3 integrin and matrix metalloprotease 2, suggesting that the leptin signaling pathway is involved in adhesion and migration processes. This study adds leptin to the repertoire of factors that mediate EMT and, for the first time, demonstrates a role for the interleukin 6 family in embryonic EMT.

Show MeSH
Related in: MedlinePlus