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Dynamic patterns of retinoic acid synthesis and response in the developing mammalian heart
J B Moss1, J Xavier-Neto, M D Shapiro
1Cardiovascular Research Center, Massachusetts General Hospital, Charlestown 02129, USA.
Abstract:
Retinoic acid (RA) has been implicated in cardiac morphogenesis by its teratogenic effects on the heart, although its role in normal cardiogenesis remains unknown. To define the parameters of RA action in cardiac morphogenesis, we analyzed the patterns of ligand synthesis, response, and inactivation in the developing mouse heart. Activation of a lacZ transgene controlled by an RA response element (RARE) was compared to the localization of the retinaldehyde-oxidizing dehydrogenase RALDH2, the earliest RA synthetic enzyme in the mouse embryo, and to the expression of a gene encoding an RA-degrading enzyme (P450RA). We observed that RALDH2 localization and RA response were virtually superimposable throughout heart development. Initially, both RALDH2 and RARE-LacZ activity were restricted to the sinus venosa in unlooped hearts, but were high in the dorsal mesocardium, while P450RA expression was restricted to the endocardium. Later stages were characterized by a sequential, noncontiguous progression of RALDH2 accumulation and RA response, from the sinus venosa to atria, dorsal-medial conotruncus, aortic arches, and the epicardium. This dynamic pattern of RA response was a direct result of localized RALDH2, since hearts of cultured embryos were uniformly competent to respond to an exogenous RA challenge. These observations support a model in which the influence of endogenous RA on heart development depends upon localized presentation of the ligand, with only limited diffusion from the source of its synthesis.
Insights
Retinoic acid (RA) plays a crucial role in heart development by being synthesized and responding in specific locations. This localized synthesis guides normal cardiac morphogenesis in developing mouse hearts.
Area of Science:
- Developmental Biology
- Molecular Biology
- Cardiovascular Research
Background:
- Retinoic acid (RA) is known for teratogenic effects on the heart, but its role in normal cardiogenesis is unclear.
- Understanding RA's precise function is key to understanding heart development.
- Previous studies highlight RA's teratogenic potential, necessitating research into its physiological role.
Purpose of the Study:
- To define the parameters of retinoic acid (RA) action during cardiac morphogenesis.
- To investigate the spatial and temporal patterns of RA synthesis, response, and inactivation in the developing mouse heart.
- To elucidate the localized nature of RA signaling in normal heart development.
Main Methods:
- Compared lacZ transgene activation (driven by an RA response element) with the localization of RALDH2 (an early RA synthetic enzyme).
- Assessed expression of P450RA (an RA-degrading enzyme) in developing mouse hearts.
- Utilized cultured embryos to test response to exogenous RA.
Main Results:
- RALDH2 localization and RA response patterns were nearly identical throughout heart development.
- Early patterns showed RALDH2 and RA response in the sinus venosa and dorsal mesocardium; P450RA was in the endocardium.
- Later stages revealed a sequential progression of RA signaling from the sinus venosa through atria, conotruncus, aortic arches, and to the epicardium.
Conclusions:
- Localized synthesis of RA by RALDH2 dictates the dynamic pattern of RA response during heart development.
- The developing heart is uniformly competent to respond to RA, indicating localized synthesis is the primary determinant of signaling.
- Endogenous RA influences heart development through localized presentation, with minimal diffusion from its synthesis site.