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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 receptor during endocardial cushion morphogenesis. Immunofluorescence staining (red) for leptin receptor 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 myocardium adjacent to the endocardial cushion (A), the endothelium overlaying the endocardial cushion (B), and the mesenchymal cells within the endocardial cushion (D).
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fig2: Spatiotemporal localization of leptin receptor during endocardial cushion morphogenesis. Immunofluorescence staining (red) for leptin receptor 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 myocardium adjacent to the endocardial cushion (A), the endothelium overlaying the endocardial cushion (B), and the mesenchymal cells within the endocardial cushion (D).

Mentions: Leptin receptor was evaluated using an antibody directed toward the intracellular domain of the long form of the receptor. Although the short forms of the receptor have signaling capabilities, they are generally thought to mediate leptin internalization for degradation, leptin transport across cell barriers, such as the blood brain barrier, or to serve as a soluble form of the receptor upon proteolytic cleavage of the extracellular domain (Uotani et al., 1999; Hileman et al., 2000; Ge et al., 2002). In the acellular expanding endocardial cushion (Fig. 2, A and B), there is cytoplasmic staining and strong perinuclear expression in the myocardium (Fig. 2 A, inset) and endocardium (Fig. 2 B, inset). This pattern is consistent with a published study on leptin receptor cellular localization (Lundin et al., 2000). In Ob-R–transfected COS cells, the majority of leptin receptors (75–95%) localize intracellularly, residing within the endoplasmic reticulum and Golgi (Lundin et al., 2000). Similar to leptin ligand, leptin receptor decreases in the myocardium as morphogenesis progresses (Fig. 2, C–F).


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 receptor during endocardial cushion morphogenesis. Immunofluorescence staining (red) for leptin receptor 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 myocardium adjacent to the endocardial cushion (A), the endothelium overlaying the endocardial cushion (B), and the mesenchymal cells within the endocardial cushion (D).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2315681&req=5

fig2: Spatiotemporal localization of leptin receptor during endocardial cushion morphogenesis. Immunofluorescence staining (red) for leptin receptor 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 myocardium adjacent to the endocardial cushion (A), the endothelium overlaying the endocardial cushion (B), and the mesenchymal cells within the endocardial cushion (D).
Mentions: Leptin receptor was evaluated using an antibody directed toward the intracellular domain of the long form of the receptor. Although the short forms of the receptor have signaling capabilities, they are generally thought to mediate leptin internalization for degradation, leptin transport across cell barriers, such as the blood brain barrier, or to serve as a soluble form of the receptor upon proteolytic cleavage of the extracellular domain (Uotani et al., 1999; Hileman et al., 2000; Ge et al., 2002). In the acellular expanding endocardial cushion (Fig. 2, A and B), there is cytoplasmic staining and strong perinuclear expression in the myocardium (Fig. 2 A, inset) and endocardium (Fig. 2 B, inset). This pattern is consistent with a published study on leptin receptor cellular localization (Lundin et al., 2000). In Ob-R–transfected COS cells, the majority of leptin receptors (75–95%) localize intracellularly, residing within the endoplasmic reticulum and Golgi (Lundin et al., 2000). Similar to leptin ligand, leptin receptor decreases in the myocardium as morphogenesis progresses (Fig. 2, C–F).

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