Role of carotenoids and retinoids during heart development

Sîrbu, Ioan Ovidiu; Chiș, Aimee Rodica; Moise, Alexander R.

doi:10.1016/j.bbalip.2020.158636

Cited by 17 publications

(15 citation statements)

References 428 publications

(364 reference statements)

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“…Retinoic acid (RA) signaling is a strong candidate for the Tbx5-dependent signal that activates endodermal Shh expression. Like Tbx5 mutants, RA deficient embryos have reduced Shh expression in the foregut ( Wang et al, 2006 ; Rankin et al, 2016 ) and manifest multiple cardiac and pulmonary defects, like Tbx5 mutants ( Zaffran et al, 2014 ; Xavier-Neto et al, 2015 ; Perl and Waxman, 2019 ; Sirbu et al, 2020 ). RA, a derivative of vitamin A, is produced in the lpm by the aldehyde dehydrogenase enzyme Aldh1a2, which converts cellular retinaldehyde into RA ( Niederreither et al, 1999 ; Metzler and Sandell, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Tbx5 drives Aldh1a2 expression to regulate a RA-Hedgehog-Wnt gene regulatory network coordinating cardiopulmonary development

Rankin

Steimle

Yang

et al. 2021

eLife

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The gene regulatory networks that coordinate the development of the cardiac and pulmonary systems are essential for terrestrial life but poorly understood. The T-box transcription factor Tbx5 is critical for both pulmonary specification and heart development, but how these activities are mechanistically integrated remains unclear. Here using Xenopus and mouse embryos, we establish molecular links between Tbx5 and retinoic acid (RA)-signaling in the mesoderm and between RA signaling and sonic hedgehog expression in the endoderm to unveil a conserved RA-Hedgehog-Wnt signaling cascade coordinating cardiopulmonary development. We demonstrate that Tbx5 directly maintains expression of aldh1a2, the RA-synthesizing enzyme, in the foregut lateral plate mesoderm via an evolutionarily conserved intronic enhancer. Tbx5 promotes posterior second heart field identity in a positive feedback loop with RA, antagonizing a Fgf8-Cyp regulatory module to restrict FGF activity to the anterior. We find that Tbx5/Aldh1a2-dependent RA signaling directly activates shh transcription in the adjacent foregut endoderm through a conserved MACS1 enhancer. Hedgehog signaling coordinates with Tbx5 in the mesoderm to activate expression of wnt2/2b, which induces pulmonary fate in the foregut endoderm. These results provide mechanistic insight into the interrelationship between heart and lung development informing cardiopulmonary evolution and birth defects.

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Section: Introductionmentioning

confidence: 99%

Tbx5 drives Aldh1a2 expression to regulate a RA-Hedgehog-Wnt gene regulatory network coordinating cardiopulmonary development

Rankin

Steimle

Yang

et al. 2021

eLife

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“…RA plays important roles in embryonic development and adult life (reviewed in [ 55 ]. RA is required during embryogenesis for anterior-posterior patterning and organogenesis [ 55 , 56 , 57 , 58 ]. For this reason, even modest changes in the levels of RA in embryonic tissues can lead to developmental defects and embryonic lethality [ 56 , 59 , 60 ].…”

Section: Transcriptional Regulation Mediated By Rar-rxrmentioning

confidence: 99%

Mechanisms of Feedback Regulation of Vitamin A Metabolism

2022

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Vitamin A is an essential nutrient required throughout life. Through its various metabolites, vitamin A sustains fetal development, immunity, vision, and the maintenance, regulation, and repair of adult tissues. Abnormal tissue levels of the vitamin A metabolite, retinoic acid, can result in detrimental effects which can include congenital defects, immune deficiencies, proliferative defects, and toxicity. For this reason, intricate feedback mechanisms have evolved to allow tissues to generate appropriate levels of active retinoid metabolites despite variations in the level and format, or in the absorption and conversion efficiency of dietary vitamin A precursors. Here, we review basic mechanisms that govern vitamin A signaling and metabolism, and we focus on retinoic acid-controlled feedback mechanisms that contribute to vitamin A homeostasis. Several approaches to investigate mechanistic details of the vitamin A homeostatic regulation using genomic, gene editing, and chromatin capture technologies are also discussed.

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“…A strong candidate for orchestrating the Tbx5-dependent cell non-autonomous activation of Shh in the foregut endoderm is retinoic acid (RA) signaling. RA deficient embryos have multiple cardiac and pulmonary defects (Zaffran et al 2014;Xavier-Neto et al 2015;Perl and Waxman, 2019;Sirbu et al 2020). RA is produced in the lpm by the enzyme Aldh1a2 (Niederreither et al 1999;Metzler and Sandell, 2016) and Aldh1a2 is co-expressed with Tbx5 in a subset of the pSHF (Hochreb et al 2003;Ryckebusch et al 2008;DeBono et al 2018).…”

Section: Introductionmentioning

confidence: 99%

TBX5 drivesAldh1a2expression to regulate a RA-Hedgehog-Wnt gene regulatory network coordinating cardiopulmonary development

Rankin

Steimle

Yang

et al. 2021

Preprint

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The gene regulatory networks that coordinate the development of the cardiac and pulmonary systems are essential for terrestrial life but poorly understood. The T-box transcription factor Tbx5 is critical for both pulmonary specification and heart development, but how these activities are mechanistically integrated remains unclear. We show that Tbx5 regulates an evolutionarily conserved retinoic acid (RA)-Hedgehog-Wnt signaling cascade coordinating cardiopulmonary development. We demonstrate that Tbx5 directly maintains expression of the RA-synthesizing enzyme Aldh1a2 in the foregut lateral plate mesoderm via an intronic enhancer that is evolutionarily conserved among terrestrial vertebrates. Tbx5 promotes posterior second heart field identity in a positive feedback loop with RA, antagonizing a Fgf8-Cyp regulatory module and restricting FGF activity to the anterior. Tbx5/Aldh1a2-dependent RA signaling also directly activates Shh transcription in the adjacent foregut endoderm through the conserved MACS1 enhancer. Epithelial Hedgehog then signals back to the mesoderm, where together with Tbx5 it activates expression of Wnt2/2b that ultimately induce pulmonary fate in the foregut endoderm. These results provide mechanistic insight into the interrelationship between heart and lung development informing cardiopulmonary evolution and birth defects.

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Role of carotenoids and retinoids during heart development

Cited by 17 publications

References 428 publications

Tbx5 drives Aldh1a2 expression to regulate a RA-Hedgehog-Wnt gene regulatory network coordinating cardiopulmonary development

Tbx5 drives Aldh1a2 expression to regulate a RA-Hedgehog-Wnt gene regulatory network coordinating cardiopulmonary development

Mechanisms of Feedback Regulation of Vitamin A Metabolism

TBX5 drivesAldh1a2expression to regulate a RA-Hedgehog-Wnt gene regulatory network coordinating cardiopulmonary development

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