Reiterative Mechanisms of Retinoic Acid Signaling during Vertebrate Heart Development

Abstract

Tightly-regulated levels of retinoic acid (RA) are critical for promoting normal vertebrate development. The extensive history of research on RA has shown that its proper regulation is essential for cardiac progenitor specification and organogenesis. Here, we discuss the roles of RA signaling and its establishment of networks that drive both early and later steps of normal vertebrate heart development. We focus on studies that highlight the drastic effects alternative levels of RA have on early cardiomyocyte (CM) specification and cardiac chamber morphogenesis, consequences of improper RA synthesis and degradation, and known effectors downstream of RA. We conclude with the implications of these findings to our understanding of cardiac regeneration and the etiologies of congenital heart defects.

GATA6 mutations in hiPSCs inform mechanisms for maldevelopment of the heart, pancreas, and diaphragm

“…Our analyses support the conclusion that CHD, pancreatic malformations and congenital diaphragmatic hernia that occur in GATA6 exon four missense mutants reflect both loss of physiologic levels of GATA6 and excessively activated RA signaling. Development of the second heart field and neural crest cell migration into the nascent outflow tract is regulated by RA signaling ( Zaffran and Kelly, 2012 ), and when inappropriate, cardiac morphogenesis is perturbed ( Perl and Waxman, 2019 ). RA signaling also regulates transcriptional signals to develop the diaphragm ( Kardon et al, 2017 ), particularly formation of the central tendon ( Coles and Ackerman, 2013 ) around which diaphragmatic myocytes are patterned.…”

Octopus insularis as a new marine model for EvoDevo

“…In other species such as Enteroctopus dofleini , the systemic heart can stop for up to 1 h without any apparent ill effects (Wells, 1979). There is extensive knowledge about the genetic pathways and cellular differentiation events related to heart development in vertebrates (Perl and Waxman, 2019; Zhang, 2019). As shown in this work, heart function during developmental stages could be easily visualized in O. insularis embryos; therefore, this octopus may be an excellent model for understanding how cephalopods and vertebrates reached similar solutions to make oxygen available to the cells in their bodies.…”

Regulating Retinoic Acid Availability during Development and Regeneration: The Role of the CYP26 Enzymes

“…In summary, inhibition of RA signalling by CYP26A1 is required for CD235+ mesodermal precursors to give rise to ventricular fates whereas atrial induction is mediated via autocrine RA signalling in RALDH2+ mesoderm. Thus, the balance between atrial versus ventricular fate induction is, in part, mediated by balance between RA synthesis (RALDH2+) and degradation expression (CYP26A1+) in two mesodermal precursor populations in a similar fashion to that exhibited in embryos [251,353], reviewed [354].…”