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GENETIC AND PHYSIOLOGICAL CONTRIBUTION OF ADRENERGIC CELLS IN HEART DEVELOPMENT

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Date Issued:
2011
Abstract/Description:
The adrenergic hormones norepinephrine (NE) and epinephrine (EPI) are essential for cardiovascular development as embryos lacking NE/EPI begin to die abruptly between embryonic days 10.5 and 11.5 due to apparent cardiac failure. The objective of this research aimed to elucidate the mechanism of embryonic fatality observed in the NE/EPI deficient mouse model. We utilized the dopamine [two]-hydroxylase knockout (Dbh-/-) mouse model, which lacks the gene and subsequent enzyme necessary for conversion of dopamine to NE. We utilized embryonic mouse hearts at E10.5 from Dbh+/+ (control) and Dbh-/- (experimental model) mice for mRNA transcript expression profiling. Gene expression data suggests a novel connection between the ability of the heart to synthesize adrenergic hormones and the gene expression of enzymes involved in the production of retinoic acid. We found a statistically significant change in transcriptional expression of the retinol binding protein-1 (Rbp-1) [+ 1.4 fold], retinol dehydrogenase 12 (Rdh-12) [+ 2.1 fold], and the beta carotene monooxygenase-1(Bcmo1) [- 2.7 fold] genes in the hearts of E10.5 Dbh-/- embryos. These genes encode enzymes responsible for the transport and enzymatic conversion of retinoic acid precursor molecules. Since alterations in retinoic acid concentration have been shown to cause mid-gestational embryonic teratogenesis and lethality, we chose to quantify retinoic acid present in the Dbh-/-embryo at E10.5. Our results showed a significantly higher concentration of retinoic acid in E10.5 Dbh-/- embryos as compared to wild-type controls. This finding indicates that altered expression of genes involved in retinoic acid synthesis lead to a physiological change in retinoic acid concentration which may contribute to the mid-gestational lethality of the Dbh-/- embryos. Previous studies have shown that adrenergic hormones are produced within the heart itself beginning early in embryonic development, but little is known about the fate and disposition of adrenergic cells within the heart at later stages and into adulthood. To investigate this, we utilized a genetic mouse model that expresses [two]-galactosidase ([two]-Gal) in cells capable of synthesizing EPI in order to identify the spatial and temporal distribution of adrenergic-derived cells in the developing heart. The model was designed so that cells capable of expressing the gene phenylethanolamine N-methyltransferase (Pnmt), which is responsible for the synthesis of epinephrine, also produce the enzyme [two]-Gal as a reporter. Evaluation of the location of these cells in the embryonic heart showed a preferential distribution at the sinoatrial node and atrioventricular sulcus at E10.5, and later at E18.5 a more widely distributed ventricular pattern was observed. In the adult heart, the right myocardium showed two small cclusters of XGAL positive cells, one near the apex and another region of the sinoatrial node. However the left heart myocardium showed XGAL positive cells throughout the left atrium and scattered through the LV where the staining appeared localized to myocytes. Interestingly, the left-sided distribution in the LV appeared to be non-random and non-uniform, since specific regions near the base, mid-section, and apex were consistently XGAL-positive. These findings suggest that adrenergic cells differentiate into cardiac muscle tissue that is predominantly found on the left side of the heart by adult stages of development. Taken collectively, this study has shown a novel connection between adrenergic hormones and RA synthesis, two crucial developmental signaling pathways in the embryonic heart. Remarkably, adrenergic derived cells were also found to persist in the adult heart where they constitute relatively large sections of the left ventricle and atrium. These findings provide important new insights into the mechanism of adrenergic actions in the developing heart and a previously unanticipated structural role for cells descending from an adrenergic lineage in the formation of left myocardial tissue.
Title: GENETIC AND PHYSIOLOGICAL CONTRIBUTION OF ADRENERGIC CELLS IN HEART DEVELOPMENT.
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Name(s): Osuala, Kingsley, Author
Ebert, Steven, Committee Chair
University of Central Florida, Degree Grantor
Type of Resource: text
Date Issued: 2011
Publisher: University of Central Florida
Language(s): English
Abstract/Description: The adrenergic hormones norepinephrine (NE) and epinephrine (EPI) are essential for cardiovascular development as embryos lacking NE/EPI begin to die abruptly between embryonic days 10.5 and 11.5 due to apparent cardiac failure. The objective of this research aimed to elucidate the mechanism of embryonic fatality observed in the NE/EPI deficient mouse model. We utilized the dopamine [two]-hydroxylase knockout (Dbh-/-) mouse model, which lacks the gene and subsequent enzyme necessary for conversion of dopamine to NE. We utilized embryonic mouse hearts at E10.5 from Dbh+/+ (control) and Dbh-/- (experimental model) mice for mRNA transcript expression profiling. Gene expression data suggests a novel connection between the ability of the heart to synthesize adrenergic hormones and the gene expression of enzymes involved in the production of retinoic acid. We found a statistically significant change in transcriptional expression of the retinol binding protein-1 (Rbp-1) [+ 1.4 fold], retinol dehydrogenase 12 (Rdh-12) [+ 2.1 fold], and the beta carotene monooxygenase-1(Bcmo1) [- 2.7 fold] genes in the hearts of E10.5 Dbh-/- embryos. These genes encode enzymes responsible for the transport and enzymatic conversion of retinoic acid precursor molecules. Since alterations in retinoic acid concentration have been shown to cause mid-gestational embryonic teratogenesis and lethality, we chose to quantify retinoic acid present in the Dbh-/-embryo at E10.5. Our results showed a significantly higher concentration of retinoic acid in E10.5 Dbh-/- embryos as compared to wild-type controls. This finding indicates that altered expression of genes involved in retinoic acid synthesis lead to a physiological change in retinoic acid concentration which may contribute to the mid-gestational lethality of the Dbh-/- embryos. Previous studies have shown that adrenergic hormones are produced within the heart itself beginning early in embryonic development, but little is known about the fate and disposition of adrenergic cells within the heart at later stages and into adulthood. To investigate this, we utilized a genetic mouse model that expresses [two]-galactosidase ([two]-Gal) in cells capable of synthesizing EPI in order to identify the spatial and temporal distribution of adrenergic-derived cells in the developing heart. The model was designed so that cells capable of expressing the gene phenylethanolamine N-methyltransferase (Pnmt), which is responsible for the synthesis of epinephrine, also produce the enzyme [two]-Gal as a reporter. Evaluation of the location of these cells in the embryonic heart showed a preferential distribution at the sinoatrial node and atrioventricular sulcus at E10.5, and later at E18.5 a more widely distributed ventricular pattern was observed. In the adult heart, the right myocardium showed two small cclusters of XGAL positive cells, one near the apex and another region of the sinoatrial node. However the left heart myocardium showed XGAL positive cells throughout the left atrium and scattered through the LV where the staining appeared localized to myocytes. Interestingly, the left-sided distribution in the LV appeared to be non-random and non-uniform, since specific regions near the base, mid-section, and apex were consistently XGAL-positive. These findings suggest that adrenergic cells differentiate into cardiac muscle tissue that is predominantly found on the left side of the heart by adult stages of development. Taken collectively, this study has shown a novel connection between adrenergic hormones and RA synthesis, two crucial developmental signaling pathways in the embryonic heart. Remarkably, adrenergic derived cells were also found to persist in the adult heart where they constitute relatively large sections of the left ventricle and atrium. These findings provide important new insights into the mechanism of adrenergic actions in the developing heart and a previously unanticipated structural role for cells descending from an adrenergic lineage in the formation of left myocardial tissue.
Identifier: CFE0003987 (IID), ucf:48653 (fedora)
Note(s): 2011-08-01
Ph.D.
Medicine, Burnett College of Biomedical Sciences
Doctorate
This record was generated from author submitted information.
Subject(s): Adrenergic hormones
Retinoic acid
cardiac development
Adrenergic derived cells
embryonic gene expression
Persistent Link to This Record: http://purl.flvc.org/ucf/fd/CFE0003987
Restrictions on Access: campus 2016-07-01
Host Institution: UCF

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