Abstract
Epicardial signaling and Rxra are required for expansion of the ventricular myocardial compact zone. Here, we examine Raldh2-/- and Rxra -/- mouse embryos to investigate the role of retinoic acid (RA) signaling in this developmental process. The heart phenotypes of Raldh2 and Rxra mutants are very similar and are characterized by a prominent defect in ventricular compact zone growth. Although RA activity is completely lost in Raldh2-/- epicardium and the adjacent myocardium, RA activity is not lost in Rxra-/- hearts, suggesting that RA signaling in the epicardium/myocardium is not required for myocardial compact zone formation. We explored the possibility that RA-mediated target gene transcription in non-cardiac tissues is required for this process. We found that hepatic expression of erythropoietin (EPO), a secreted factor implicated in myocardial expansion, is dependent on both Raldh2 and Rxra. Chromatin immunoprecipitation studies support Epo as a direct target of RA signaling in embryonic liver. Treatment of an epicardial cell line with EPO, but not RA, upregulates Igf2. Furthermore, both Raldh2-/- and Rxra-/- hearts exhibit downregulation of Igf2 mRNA in the epicardium. EPO treatment of cultured Raldh2-/- hearts restores epicardial Igf2 expression and rescues ventricular cardiomyocyte proliferation. We propose a new model for the mechanism of RA-mediated myocardial expansion in which RA directly induces hepatic Epo resulting in activation of epicardial Igf2 that stimulates compact zone growth. This RA-EPO-IGF2 signaling axis coordinates liver hematopoiesis with heart development.
Original language | English (US) |
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Pages (from-to) | 139-148 |
Number of pages | 10 |
Journal | Development |
Volume | 138 |
Issue number | 1 |
DOIs | |
State | Published - Jan 1 2011 |
Externally published | Yes |
Keywords
- Epicardium
- Epo
- Erythropoietin
- Heart development
- Igf2
- Liver
- Mouse
- Myocardial compact zone
- Raldh2
- Retinoic acid
ASJC Scopus subject areas
- Molecular Biology
- Developmental Biology