Anterior Endoderm Is Sufficient to Rescue Foregut Apoptosis and Heart Tube Morphogenesis in an Embryo Lacking Retinoic Acid

Ghatpande, Satish; Ghatpande, Ashwini; Zile, Maija H.; Evans, Todd

doi:10.1006/dbio.1999.9601

Cited by 56 publications

(43 citation statements)

References 62 publications

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“…More likely it is the feedback repression that Nkx2.5 normally imposes on Bmp2/ Smad signaling (31), which when relieved may improve the RA deficiency phenotype. Transplantation of W T foregut endoderm, or exogenous supply of BMP2 and Gata4, can restore heart morphology in vitamin A-deficient quail embryos (35,36). Although Bmp2 expression indeed appears up-regulated in Nkx2.5;Raldh2 compound mutants, further genetic strategies are required to clarify the precise manner by which these two signaling pathways interact.…”

Section: Discussionmentioning

confidence: 99%

Retinoic acid deficiency alters second heart field formation

Ryckebüsch

Wang

Bertrand

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

189

240

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Retinoic acid (RA), the active derivative of vitamin A, has been implicated in various steps of cardiovascular development. The retinaldehyde dehydrogenase 2 (RALDH2) enzyme catalyzes the second oxidative step in RA biosynthesis and its loss of function creates a severe embryonic RA deficiency. Raldh2 ؊/؊ knockout embryos fail to undergo heart looping and have impaired atrial and sinus venosus development. To understand the mechanism(s) producing these changes, we examined the contribution of the second heart field (SHF) to pharyngeal mesoderm, atria, and outflow tract in Raldh2 ؊/؊ embryos. RA deficiency alters SHF gene expression in two ways. First, Raldh2 ؊/؊ embryos exhibited a posterior expansion of anterior markers of the SHF, including Tbx1, Fgf8, and the Mlc1v-nlacZ-24/Fgf10 reporter transgene as well as of Islet1. This occurred at early somite stages, when cardiac defects became irreversible in an avian vitamin A-deficiency model, indicating that endogenous RA is required to restrict the SHF posteriorly. Explant studies showed that this expanded progenitor population cannot differentiate properly. Second, RA up-regulated cardiac Bmp expression levels at the looping stage. The contribution of the SHF to both inflow and outflow poles was perturbed under RA deficiency, creating a disorganization of the heart tube. We also investigated genetic cross-talk between Nkx2.5 and RA signaling by generating double mutant mice. Strikingly, Nkx2.5 deficiency was able to rescue molecular defects in the posterior region of the Raldh2 ؊/؊ mutant heart, in a gene dosage-dependent manner.retinoids ͉ retinaldehyde dehydrogenase 2 ͉ heart development ͉ Nkx2.5 ͉ FGF8

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Section: Discussionmentioning

confidence: 99%

Retinoic acid deficiency alters second heart field formation

Ryckebüsch

Wang

Bertrand

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

189

240

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“…The action of retinoids, which are mediated by two distantly related families of nuclear retinoid receptors, RARs and RXRs, has been implicated in controlling cell proliferation, differentiation and apoptosis (11,19,27,28), including involvement in cardiac development and function (11,21,29). These studies show that RAR␣ is almost ubiquitously expressed in embryos at all stages, while the expressions of RXR␣ and RXR␤ are highest at E11.5-12.5 (30,31).…”

Section: Discussionmentioning

confidence: 92%

Ectopic Expression of Retinoic Acid Receptors and Change of Myocardial Structure in the Offspring Heart with Vitamin A Deficiency

Feng

Yin

et al. 2012

J Nutr Sci Vitaminol

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309Vitamin A (VA) and its biological derivatives (the retinoids) play diverse roles in physiology, ranging from incorporation into vision pigments to controlling transcription of a host of important genes, as evidenced by the myriad of disorders that accompany defi ciency or excess states. Vitamin A defi ciency (VAD) is a public health problem in more than half of all countries, especially in developing countries, hitting hardest young children and pregnant women. According to the data from WHO, approximately 15% of pregnant women are estimated to be VAD all over the world (1). Maternal insuffi ciency of VA during pregnancy results in fetal death or severe abnormalities in the offspring, including aberrant heart development (2-4).The VA active form, retinoic acid (RA), which acts as a ligand for the nuclear receptors the retinoic acid receptors (RARs) (RAR␣, -␤, and -␥) and the retinoic X receptors (RXRs) (RXR␣, -␤, and -␥), distinctly regulates embryonic development. It is an accepted fact that RARs and RXRs are indispensable for embryonic patterning and organogensis, including cardiogenesis (5-8). Some studies show that the RAR␥ gene is at very high levels in the endocardial cushions of the midgestation embryo (9). Data from Mangelsdorf et al. (10) show that the expression of RXR␣ and RXR␤ are highest in the whole embryo at midgestion (embryonic days 11.5-12.5), while RXR␥ expression peaks slightly later (embryonic days 13.5-14.5). Kastner et al. indicate that at least four distinct retinoid receptors (RXR␣, RXR␤, RAR␣ and RAR␤) are likely involved in controlling the ventricular myocardium development (11). Ectopic Expression of Retinoic Acid Receptors and Change of Myocardial Structure in the Offspring Heart withVitamin A Defi ciency Summary Vitamin A is a key micronutrient required during crucial stages of embryonic development and vitamin A defi ciency (VAD) results in embryonic heart malformation. The pleiotropic functions of vitamin A are mediated by specifi c nuclear receptors: the retinoic acid receptors (RAR␣, -␤, and -␥) and the retinoic X receptors (RXR␣, -␤, and -␥). The action of nuclear receptors has been implicated in controlling of cell proliferation, differentiation and apoptosis, and the expressions of these receptor genes are regulated by retinoic acid levels during the early stages of embryonic development. GATA-4 is one of the earliest transcription factors expressed in developing cardiac cells. However, the functional links of specifi c nuclear receptors to heart development in VAD embryos are not clearly understood. In our study, weaning female Sprague-Dawley rats were fed a modifi ed diet containing different concentrations of vitamin A according to the American Institute of Nutrition 93 Growth Purifi ed Diet. After 10-wk feeding, the female rats were mated with normal male rats, and a portion of them were transferred to a diet with enough added vitamin A for the pregnancy cycle. The embryo hearts were dissected out at embryonic day 13.5 (E13.5) to study the expression of RARs, RXRs and...

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“…In VAD embryos, the reduction in levels of Gata4 correlates with an abnormal and excessive pattern of apoptosis in the associated foregut endoderm (Ghatpande et al, 2000). Bmp2/4 treatment is known to induce Gata4 expression (Andree et al, 1998;Schlange et al, 2000), and so we tested if this is also sufficient to rescue foregut apoptosis.…”

Section: Bmp2 Is Sufficient To Rescue the Survival Of Anterior Endodementioning

confidence: 99%

“…Endoderm transplant experiments suggested that a factor in addition to RA is required for survival of presumptive foregut endoderm, which supports normal cardiogenesis (Ghatpande et al, 2000). As a primary candidate for such a factor, we considered BMPs for several reasons.…”

Section: Vad Embryos Are Deficient For Expression Levels Of Bmp2mentioning

confidence: 99%

“…Explanting normal anterior (presumptive foregut) endoderm can rescue the VAD cardiac inflow tract phenotype, although RA alone is not sufficient to explain this, since non-rescuing posterior endoderm also has RA. Therefore, we suggested that RA normally induces in anterior endoderm a cardiogenic factor important for Gata4 expression and posterior heart tube development (Ghatpande et al, 2000). BMPs are excellent candidates for this unknown factor, since the pathway has been linked to Gata4 expression, and there is precedence in other systems, for example the limb bud, for induction of BMP synthesis by RA.…”

Section: Introductionmentioning

confidence: 98%

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Bmp2 and Gata4 function additively to rescue heart tube development in the absence of retinoids

Ghatpande

Brand

Zile

et al. 2006

Developmental Dynamics

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We used the vitamin A-deficient (VAD) quail model to investigate the retinoid-dependent mechanism that regulates heart tube development. We showed previously that decreased levels of Gata4 in cardiogenic mesoderm and endoderm correlate with the cardiomyopathy caused by VAD, but that this could be rescued by transplanting normal anterior endoderm. Bmp2 is a known cardiogenic factor that is expressed normally in lateral plate mesoderm and cardiac-associated pharyngeal endoderm. Here we show that (like Gata4) transcripts encoding Bmp2 and BMP-dependent signaling activity are decreased throughout the heartforming region of the VAD embryo. Addition of Bmp2 protein or forced expression of Gata4 in cultured VAD embryos leads to a partial rescue of the cardiomyopathy, and addition of both Bmp2 and Gata4 has an additive positive effect. Our data are consistent with a requirement for retinoid signaling to maintain expression of Bmp2, which regulates Gata4, and in addition acts with Gata4 to regulate genes important for normal morphogenesis of the primitive heart tube.

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Anterior Endoderm Is Sufficient to Rescue Foregut Apoptosis and Heart Tube Morphogenesis in an Embryo Lacking Retinoic Acid

Cited by 56 publications

References 62 publications

Retinoic acid deficiency alters second heart field formation

Retinoic acid deficiency alters second heart field formation

Ectopic Expression of Retinoic Acid Receptors and Change of Myocardial Structure in the Offspring Heart with Vitamin A Deficiency

Bmp2 and Gata4 function additively to rescue heart tube development in the absence of retinoids

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