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2011 | 58 | 1 | 19-29
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Expression of cellular retinoic acid-binding protein I and II (CRABP I and II) in embryonic mouse hearts treated with retinoic acid

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Cellular retinoic acid binding proteins are considered to be involved in retinoic acid (RA) signaling pathways. Our aim was to compare the expression and localization of cellular retinoic acid binding proteins I and II (CRABP I and II) in embryonic mouse hearts during normal development and after a single teratogenic dose of RA. Techniques such as real-time PCR, RT-PCR, Western blots and immunostaining were employed to examine hearts from embryos at 9-17 dpc. RA treatment at 8.5dpc affects production of CRABP I and II in the heart in the 48-h period. Changes in expression of mRNA for retinaldehyde dehydrogenase II (Raldh2), Crabp1 and Crabp2 genes also occur within the same time window (i.e. 10-11dpc) after RA treatment. In the embryonic control heart these proteins are localized in groups of cells within the outflow tract (OT), and the atrioventricular endocardial cushions. A gradient of labeling is observed with CRABP II but not for CRABP I along the myocardium of the looped heart at 11 dpc; this gradient is abolished in hearts treated with RA, whereas an increase of RALDH2 staining has been observed at 10 dpc in RA-treated hearts. Some populations of endocardial endothelial cells were intensively stained with anti-CRABP II whereas CRABP I was negative in these structures. These results suggest that CRABP I and II are independently regulated during heart development, playing different roles in RA signaling, essential for early remodeling of the heart tube and alignment of the great arteries to their respective ventricles.
Physical description
  • Department of Pathological Anatomy, Medical University of Warsaw, Warszawa, Poland
  • Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
  • Department of Histology and Embryology, Medical University of Warsaw, Warszawa, Poland
  • Department of Molecular Biology, Institute of Cardiology, Warszawa, Poland
  • Department of Pathological Anatomy, Medical University of Warsaw, Warszawa, Poland
  • Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
  • Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
  • Department of Pathological Anatomy, Medical University of Warsaw, Warszawa, Poland
  • Aström A, Tavakkol A, Pettersson U, Cromie M, Elder JT, Voorhees JJ (1991) Molecular cloning of two human cellular retinoic acid-binding proteins (CRABP). Retinoic acid-induced expression of CRABP-II but not CRABP-I in adult human skin in vivo and in skin fibroblasts in vitro. J Biol Chem 266: 17662-17666.
  • Berggren K, McCaffery P, Dräger U, Forehand CJ (1999) Differential distribution of retinoic acid synthesis in the chicken embryo as determined by immunolocalization of the retinoic acid synthetic enzyme, RALDH-2. Dev Biol 210: 288-304.
  • Berggren K, Ezerman EB, McCaffery P, Forehand CJ (2001) Expression and regulation of the retinoic acid synthetic enzyme RALDH-2 in the embryonic chicken wing. Dev Dyn 222: 1-16.
  • Bernlohr DA, Simpson MA, Hertzel AV, Banaszak LJ (1997) Intracellular lipid-binding proteins and their genes. Annu Rev Nutr 17: 277-303.
  • Bouman HGA, Broekhuizen MLA, Baasten AMJ, Gittenberger-de Groot AC, Wenink ACG (1995) Spectrum of looping disturbances in stage 34 chicken hearts after retinoic acid treatment. Anat Rec 243: 101-108.
  • Boylan JF, Gudas LJ (1992) The level of CRABP-I expression influences the amounts and types of all-trans-retinoic acid metabolites in F9 teratocarcinoma stem cells. J Biol Chem 267: 21486-21491.
  • Bucco RA, Zheng WL, Wardlaw SA, Davis JT, Sierra-Rivera E, Osteen KG, Melner MH, Kakkad BP, Ong DE (1996) Regulation and localization of cellular retinol-binding protein, retinol-binding protein, cellular retinoic acid-binding protein (CRABP) and CRABP II in the uterus of the pseudopregnant rat. Endocrinology 137: 3111-3122.
  • Buckingham M, Meilhac S, Zaffran S (2005) Building the mammalian heart from two sources of myocardial cells. Nat Rev Genet 6: 826-835.
  • Collop AH, Broomfield JAS, Chandratana RAS, Yong Z, Deimling SJ, Kolker SJ, Weeks DL, Drysdale TA (2006) Retinoic acid signaling is essential for formation of the heart tube in Xenopus. Dev Biol 291: 96-109.
  • Dekker EJ, Vaessen MJ, van den Berg C, Timmermans A, Godsave S, Holling T, Nieuwkoop P, Geurts van Kessel A, Durston A (1994) Overexpression of a cellular retinoic acid binding protein (xCRABP) causes anteroposterior defects in developing Xenopus embryos. Development 120: 973-985.
  • Delva L, Bastie Jean-Nöel, Rochette-Egly C, Kraďba R, Balitrand N, Despouy G, Chambon P, Chomienne C (1999) Physical and functional interactions between cellular retinoic acid binding protein II and the retinoic acid-dependent nuclear complex. Mol Cell Biol 19: 7158-7167.
  • Dingle JT, Fell HB, Goodman DS (1972) The effect of retinol and of retinol-binding protein on embryonic skeletal tissue in organ culture. J Cell Sci 11: 393-402.
  • Dong D, Ruuska SE, Levinthal DJ, Noy N (1999) Distinct roles for cellular retinoic acid-binding proteins I and II in regulating signaling by retinoic acid. J Biol Chem 274: 23695-23698.
  • Durand B, Saunders M, Leroy P, Leid M, Chambon P (1992) All-trans and 9-cis retinoic acid induction of CRABP II transcription is mediated by RAR-RXR heterodimers bound to DR1 and DR2 repeated motifs. Cell 71: 73-85.
  • Gaub MP, Lutz Y, Ghyselinck NB, Scheuer I, Pfister V, Chambon P, Rochette-Egly C (1998) Nuclear detection of cellular retinoic acid binding proteins I and II with new antibodies. J Histochem Cytochem 46: 1103-1111.
  • Giguére V, Lyn S, Yip P, Siu CH, Amin S (1990) Molecular cloning of cDNA encoding a second cellular retinoic acid-binding protein. Proc Natl Acad Sci USA 87: 6233-6237.
  • Hildreth V, Webb S, Bradshaw L, Brown NA, Anderson RH, Henderson DJ (2008) Cells migrating from the neural crest contribute to the innervation of the venous pole of the heart. J Anat 212: 1-11.
  • Hoover LL, Burton EG, Brooks BA, Kubalak SW (2008) The expanding role for retinoid signaling in heart development. ScientificWorldJournal 8: 194-211.
  • Hutson MR, Zhang P, Stadt HA, Sato AK, Li YX, Burch J, Creazzo TL, Kirby ML (2006) Cardiac arterial pole alignment is sensitive to FGF8 signaling in the pharynx. Dev Biol 295: 486-497.
  • Ilagan R, Abu-Issa R, Brown D, Yang YP, Jiao K, Schwartz RJ, Klingensmith J, Meyers EN (2006) Fgf8 is required for anterior heart field development. Development 133: 2435-2445.
  • Jiang X, Rowitch DH, Soriano P, McMahon AP, Sucov HM (2000) Fate of the mammalian cardiac neural crest. Development 127: 1607-1616.
  • Kalter H, Warkany J (1961) Experimental production of congenital malformations in strains of inbred mice by maternal treatment with hypervitaminosis A. Am J Pathol 38: 1-21.
  • Kang I-O, Sucov HM (2005) Convergent proliferative response and divergent morphogenic pathways induced by epicardial and endocardial signaling in fetal heart development. Mech Dev 122: 57-65.
  • Kastner P, Grondona JM, Mark M, Gansmuller A, LeMeur M, Decimo D, Vonesh JL, Dolle P, Chambon P (1994) Genetic analysis of RXR alpha developmental function: convergence of RXR and RAR signaling pathways in heart and eye morphogenesis. Cell 78: 987-1003.
  • Kelly RG, Brown NA, Buckingham ME (2001) The arterial pole of the mouse heart forms from Fgf10-expressing cells in pharyngeal mesoderm. Dev Cell 1: 435-440.
  • Kleinjan DA, Dekker S, Vaessen MJ, Grosveld FG (1997) Regulation of the CRABP-I gene during mouse embryogenesis. Mech Dev 67: 157-69.
  • Kleinjan DA, Dekker S, Guy JA, Grosveld FG (1998) Cloning and sequencing of the CRABP-I locus from chicken and pufferfish: analysis of the promoter regions in transgenic mice. Transgenic Res 7: 85-94.
  • Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227: 680-685.
  • Lammer EJ, Chen DT, Hoar RM, Agnish ND, Benke PJ, Braun JT, Curry CJ, Fernhoff PM, Grix AW Jr, Lott IT (1985) Retinoic acid embryopathy. N Engl J Med 313: 837-841.
  • Lampron C, Rochette-Egly C, Gorry P, Dolle P, Mark M, Lufkin T, Le Meur M, Chambon P (1995) Mice deficient in cellular retinoic acid binding protein II (CRABP II) or in both CRABPI and CRABPII are essentially normal. Development 121: 539-548.
  • Lavine KJ, Yu K, White AC, Zhang X, Smith C, Partanen J, Ornitz DM (2005) Endocardial and epicardial derived FGF signals regulate myocardial proliferation and differentiation in vivo. Dev Cell 8: 85-95.
  • Lee YM, Kim JS, Han SY, Park KL, Jang SJ, Seo JW (1998) Abnormal ventricular looping and abnormal laterality of the atrial chambers are the main morphogenetic mechanisms of the cardiac lesions in cultured rat embryos treated with retinoic acid. J Korean Med Sci 13: 117-122.
  • Leonard L, Horton C, Maden M, Pizzey JA (1995) Anteriorization of CRABP-I expression by retinoic acid in the developing mouse central nervous system and its relationship to teratogenesis. Dev Biol 168: 514-528.
  • Lin S-C, Dollé P, Ryckebüsch L, Noseda M, Zaffran S, Schneider MD, Niederreither K (2010) Endogenous retinoic acid regulates cardiac progenitor differentiation. Proc Natl Acad Sci USA 107: 9234-9239.
  • Lyn S, Giguére V (1994) Localization of CRABP-I and CRABP-II mRNA in the early mouse embryo by whole mount in situ hybridization: implications for teratogenesis and neural development. Dev Dyn 199: 280-291.
  • Maden M (1994) Distribution of cellular retinoic acid binding proteins I and II in the chick embryo and their relationship to teratogenesis. Teratology 50: 294-301.
  • Maden M, Ong DE, Summerbell D, Chytil F (1988) Spatial distribution of cellular protein binding to retinoic acid in the chick limb bud. Nature 335: 733-735.
  • Maden M, Ong DE, Chytil F (1990) Retinoid-binding protein distribution in the developing mammalian nervous system. Development 109: 75-80.
  • Maden M, Hunt P, Eriksson U, Kuroiwa A, Krumlauf R, Summerbell D (1991) Retinoic acid-binding protein, rhombomeres and the neural crest. Development 111: 35-44.
  • McCaffery P, Dräger UC (2000) Regulation of retinoic acid signaling in the embryonic nervous system: a master differentiation factor. Cytokine Growth Factor Rev 11: 233-249.
  • Mjaatvedt CH, Nakaoka T, Moreno-Rodriguez R, Norris RA, Kern MJ, Eisenberg CA, Turner D, Markwald RR (2001) The outflow tract of the heart is recruited from a novel heart-forming field. Dev Biol 238: 97-109.
  • Moss JB, Xavier-Neto J, Shapiro MD, Nayeem SM, McCaffery P, Dräger UC, Rosenthal N (1998) Dynamic patterns of retinoic acid synthesis and response in the developing mammalian heart. Dev Biol 199: 55-71.
  • Nakajima Y, Hiruma T, Nakazawa M, Morishima M (1996) Hypoplasia of cushion ridges in the proximal outflow tract elicits formation of a right ventricle-to-aortic route in retinoid acid-induced complete transposition of the great arteries in the mouse: scanning electron microscopic observations of corrosion cast models. Anat Rec 245: 76-82.
  • Nakajima Y, Morishima M, Nakazawa M, Momma K, Nakamura H (1997) Distribution of fibronectin, type I collagen, type IV collagen and laminin in the cardiac jelly of the mouse embryonic heart with retinoic acid-induced complete transposition of the great arteries. Anat Rec 249: 478-485.
  • Napoli JL (1999) Interactions of retinoid binding proteins and enzymes in retinoid metabolism. Biochem Biophys Acta 1440: 139-162.
  • Niederreither K, Vermot J, Messaddeq N, Schuhbaur B, Chambon P, Dollé P (1997a) Embryonic retinoic acid synthesis is essential for heart morphogenesis in the mouse. Development 128: 1019-1031.
  • Niederreither K, McCaffery P, Dräger UC, Chambon P, Dollč P (1997b) Restricted expression and retinoic acid-induced downregulation of the retinaldehyde dehydrogenase type 2 (RALDH-2) gene during mouse development. Mech Dev 62: 67-78.
  • Niederreither K, Subbarayan V, Dollé P, Chambon P (1999) Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. Nat Genet 21: 444-448.
  • Ong DE, Newcomer ME, Chytil F (1994) Cellular retinoid-binding proteins. In The Retinoids: Biology, Chemistry and Medicine. Sporn MB, Roberts AB, Goodman DS, eds, 2nd edn, pp 283-317. Raven Press, New York.
  • Park EJ, Ogden LA, Talbot A, Evans S, Cai CL, Black BL, Frank DU, Moon AM (2006) Required, tissue-specific roles for Fgf8 in outflow tract formation and remodeling. Development 133: 2419-2433.
  • Perez-Castro AV, Toth-Rogler LE, Wei LN, Nguyen-Huu MC (1989) Spatial and temporal pattern of expression of the cellular retinoic acid-binding protein and the cellular retinol-binding protein during mouse embryogenesis. Proc Natl Acad Sci USA 86: 8813-8817.
  • Poelmann RE, Gittenberger-de Groot AC (1999) A Subpopulation of apoptosis-prone cardiac neural crest cells targets to the venous pole: multiple functions in heart development? Dev Biol 207: 271-286.
  • Rochais F, Mesbach K, Kelly RG (2009) Signaling pathways controlling second heart field development. Circ Res 104: 933-942.
  • Rosa FW, Wilk AL, Kelsey FO (1986) Teratogen update: vitamin A congeners. Teratology 33: 355-364.
  • Ross SA, McCaffery PJ, Dräger U, De Luca LM (2000) Retinoids in embryonal development. Physiol Rev 80: 1021-1054.
  • Ruberte E, Dolle P, Krust A, Zelent A, Morrisss-Kay GM, Chambon P (1990) Specific spatial and temporal distribution of retinoic acid receptor gamma transcripts during mouse embryogenesis. Development 108: 213-222.
  • Ruberte E, Dolle P, Chambon P, Morrisss-Kay GM (1991) Retinoic acid receptors and cellular retinoid binding proteins. II. Their differential pattern of transcription during early morphogenesis in mouse embryos. Development 111: 45-60.
  • Ruberte E, Friederich V, Morriss-Kay GM, Chambon P (1992) Differential distribution patterns of CRABP I and CRABP II transcripts during mouse embryogenesis. Development 115: 973-987.
  • Ryckebusch L, Wang Z, Bertrand N, Lin SCC, Chi X, Schwartz R, Zaffran S, Neiderreither K (2008) Retinoic acid deficiency alters second heart field formation. Proc Natl Acad Sci USA 105: 2913-2918.
  • Sinning AR (1998) Role of vitamin A in the formation of congenital heart defects Anat Rec (New Anat) 253: 147-153.
  • Sirbu IO, Zhao X, Duester G (2008) Retinoic acid controls heart anteroposterior patterning by downregulating Isla1 through the Fgf8 pathway. Dev Dyn 237: 1627-1635.
  • Sucov HM, Dyson E, Gumeringer CL, Price J, Chien KR, Evans RM (1994) RXR alpha mutant mice establish a genetic basis for vitamin A signaling in heart morphogenesis. Genes Dev 8: 1007-1018.
  • Theodosiou M, Laudet V, Schubert M (2010) From carrot to clinic: on overview of the retinoic acid signaling pathway. Cell Mol Life Sci 67: 1423-1445.
  • Vaessen M-J, Meijers JHC, Bootsma D, van Kessel AG (1990) The cellular retinoic-acid-binding protein is expressed in tissues associated with retinoic-acid-induced malformations. Differentiation 110: 371-378.
  • Vermot J, Messaddeq N, Neiderreither K, Dierich A, Dollé P (2006) Rescue of morphogenetic defects and of retinoic acid signaling in retinaldehyde dehydrogenase 2 (Raldh2) mouse mutants by chimerism with wild-type cells. Differentiation 74: 661-668.
  • Waldo KL, Hutson MR, Zdanowicz M, Stadt HA, Zdanowicz J, Kirby ML (2005) Cardiac neural crest is necessary for normal addition of the myocardium to the arterial pole from the secondary heart field. Dev Biol 281: 66-77.
  • Wang Z, Zhai W, Richardson JA, Olson EN, Meneses JJ, Firpo MT, Kang C, Skarnes WC, Tjian R (2004) Polybromo protein BAF180 functions in mammalian cardiac chamber maturation. Genes Dev 18: 3106-3116.
  • Waxman JS, Keegan BR, Roberts RW, Poss KD, Yelon D (2008) Hoxb5b acts downstream of retinoic acid signaling in the forelimb field to restrict heart field potential in zebrafish. Dev Cell 15: 923-934.
  • Williams SS, Mear JP, Liang HC, Potter SS, Aronow BJ, Colbert MC (2004) Large-scale reprogramming of cranial neural crest gene expression by retinoic acid exposure. Physiol Genomics 19: 184-197.
  • Wilson JG, Roth CB, Warkany J (1953) An analysis of the syndrome of malformations included by maternal vitamin A deficiency. Effects of restoration of vitamin A at various times during gestation. Am J Anat 92: 189-217.
  • Xavier-Neto J, Shapiro MD, Houghton L, Rosenthal N (2000) Sequential programs of retinoic acid synthesis in the myocardial and epicardial layers of the developing avian heart. Dev Biol 219: 129-141.
  • Yasui H, Nakazawa M, Morishima M, Miyagawa-Tomita S, Momma K (1995) Morphological observations on the pathogenic process of transposition of the great arteries induced by retinoic acid in mice. Circulation 91: 2478-2486.
  • Yasui H, Nakazawa M, Morishima M, Ando M, Takao A, Aikawa E (1997) Cardiac outflow tract septation process in the mouse model of transposition of the great arteries. Teratology 55: 353-363.
  • Yasui H, Morishima M, Nakazawa M, Ando M, Aikawa E (1999) Developmental spectrum of cardiac outflow tract anomalies encompassing transposition of the great arteries and dextroposition of the aorta: pathogenic effect of extrinsic retinoic acid in the mouse embryo. Anat Rec 254: 253-260.
  • Yelbuz TM, Waldo KL, Kumiski DH, Stadt HA, Wolfe RR, Leatherbury L, Kirby ML (2002) Shortened outflow tract leads to altered cardiac looping after neural crest ablation. Circulation 106: 504-510.
  • Zhao D, McCaffery P, Ivins KJ, Neve RL, Hogan P, Chin WW, Dräger UC (1996) Molecular identification of a major retinoic-acid synthesizing enzyme, a retinaldehyde-specific dehydrogenase. Eur J Biochem 240: 15-22.
  • Zhelyaznik N, Schrage K, McCaffery P, Mey J (2003) Activation of retinoic acid signaling after sciatic nerve injury: up-regulation of cellular retinoid binding proteins. Eur J Neurosci 18: 1033-1040.
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