Retinoic acid (RA), the active metabolite of vitamin A, is an important regulator of cell proliferation, embryonic/fetal development, and adult homeostasis. Mice that are deficient for Raldh2, an enzyme critically involved in the synthesis of RA from retinaldehyde, indicate that RA is necessary for several events in heart development. These include atrial outgrowth, ventricular trabeculation and proliferation, and left-right looping morphogenesis.
The aims of this study are to distinguish which of these RA function(s) are intrinsic or extrinsic to the heart lineage. RA function(s) during later stages of heart differentiation (or postnatal life) cannot be studied in these mutants. A combination of conditional knockout and transgenic overexpression strategies will be used to alter RA levels specifically in the cardiac/epicardial lineage. In combination, these models will allow to determine which of the events controlled by RA are intrinsic (""""""""cell-autonomous"""""""") or extrinsic to the heart tube proper. The inducible transgenic mutants that will be created will also be useful to examine later role(s) of RA in ventricular differentiation. Finally, a microarray approach has been employed revealing novel targets of RA-dependent heart development and possible signal transduction pathways. These potential targets will be examined in each genetic mutant. Since variations in vitamin A levels contribute to human congenital heart malformations, the information gained in these studies may allow us to design better prenatal strategies to prevent such malformations. Moreover, since retinoids are potent regulators of cell proliferation, understanding downstream signaling could open up new strategies to reinitiate the regenerative capacity of the heart postnatally. The following questions will be addressed in this proposal: 1) Is RA acting directly on cardiac cells (i.e. in a cell-autonomous manner) to regulate atrial and sinus venosus outgrowth programs? 2) Do alterations of RA levels have latter consequences for ventricular development? 3) What molecular pathways regulate RA-dependent ventricular proliferation? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL070733-03
Application #
7148068
Study Section
Special Emphasis Panel (ZRG1-CDD (01))
Program Officer
Schramm, Charlene A
Project Start
2004-12-15
Project End
2009-11-30
Budget Start
2006-12-01
Budget End
2007-11-30
Support Year
3
Fiscal Year
2007
Total Cost
$320,012
Indirect Cost
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Paschaki, Marie; Lin, Song-Chang; Wong, Rebecca Lee Yean et al. (2012) Retinoic acid-dependent signaling pathways and lineage events in the developing mouse spinal cord. PLoS One 7:e32447
Bertrand, Nicolas; Roux, Marine; Ryckebusch, Lucile et al. (2011) Hox genes define distinct progenitor sub-domains within the second heart field. Dev Biol 353:266-74
Dolle, Pascal; Fraulob, Valerie; Gallego-Llamas, Jabier et al. (2010) Fate of retinoic acid-activated embryonic cell lineages. Dev Dyn 239:3260-74
Ryckebusch, Lucile; Bertrand, Nicolas; Mesbah, Karim et al. (2010) Decreased levels of embryonic retinoic acid synthesis accelerate recovery from arterial growth delay in a mouse model of DiGeorge syndrome. Circ Res 106:686-94
Lin, Song-Chang; Dolle, Pascal; Ryckebusch, Lucile et al. (2010) Endogenous retinoic acid regulates cardiac progenitor differentiation. Proc Natl Acad Sci U S A 107:9234-9
Norden, Julia; Grieskamp, Thomas; Lausch, Ekkehart et al. (2010) Wt1 and retinoic acid signaling in the subcoelomic mesenchyme control the development of the pleuropericardial membranes and the sinus horns. Circ Res 106:1212-20
Ryckebusch, Lucile; Wang, Zengxin; Bertrand, Nicolas et al. (2008) Retinoic acid deficiency alters second heart field formation. Proc Natl Acad Sci U S A 105:2913-8
Niederreither, Karen; Dolle, Pascal (2008) Retinoic acid in development: towards an integrated view. Nat Rev Genet 9:541-53
Ribes, Vanessa; Wang, Zengxin; Dolle, Pascal et al. (2006) Retinaldehyde dehydrogenase 2 (RALDH2)-mediated retinoic acid synthesis regulates early mouse embryonic forebrain development by controlling FGF and sonic hedgehog signaling. Development 133:351-61
Wang, Zengxin; Dolle, Pascal; Cardoso, Wellington V et al. (2006) Retinoic acid regulates morphogenesis and patterning of posterior foregut derivatives. Dev Biol 297:433-45