Retinoic acid is clearly important for the development of the heart.

Retinoic acid is clearly important for the development of the heart. between multiple signaling systems is required for specification and patterning of the heart including the signaling pathway (Foley and Mercola 2005 Pandur et al. 2002 Schneider and Mercola 2001 fibroblast growth element signaling (Alsan and Schultheiss 2002 bone morphogenetic protein signaling (Breckenridge et al. 2001 and the Notch Rabbit polyclonal to Anillin. signaling pathway (Rones et al. 2000 Retinoic acid (RA) is also essential in the patterning and development of the heart. RA the active form of vitamin A binds to RA receptors (RARα β and γ) and their heterodimeric partner users of the retinoid X receptor family (RXRα β and γ). This complex functions as a ligand-activated transcription element binding to retinoic acid response elements (RAREs) of target genes and it is essential for many aspects of embryonic development (Glass and Rosenfeld 2000 Ross et al. 2000 Zile 2001 In the embryonic heart RA signaling is definitely primarily mediated through the RARα receptor with a minor component of the transmission coming through the RARβ receptor (Kastner et al. 1997 The enzyme primarily responsible for RA synthesis retinaldeyde dehydrogenase 2 (RALDH2) is definitely expressed adjacent to the developing sino-atrial region during early cardiogenesis (Chen et al. 2001 Hochgreb et al. 2003 Xavier-Neto et al. 1999 suggesting that a gradient of RA may be generated along the anterior-posterior axis of the heart tube. Embryos that have experienced RA signaling attenuated have a variety of cardiac phenotypes indicating multiple tasks for RA in cardiogenesis. In zebrafish embryos that lack RA signaling have an excess of cardiomyocytes indicating that RA limits the pool of cardiac progenitors in the cardiac forming region (Keegan et al. 2005 Loss of function experiments in mammalian embryos produced by genetic ablation of RA receptors or RALDH2 (Niederreither et al. 2001 have shown that RA is necessary for IWP-3 normal cardiac morphogenesis and anterior-posterior patterning of the heart tube (Hochgreb et al. 2003 Iulianella and Lohnes 2002 Kastner et al. 1997 Sucov et al. 1994 Early developmental problems resulting from reduced RA signaling include irregular cardiac looping modified sino-atrial development and prematurely differentiated ventricular cardiomyocytes (Hochgreb et al. 2003 Niederreither et al. 2001 Exclusion of RA from your ventricle region is essential for formation of this region in early cardiogenesis (Rosenthal and Xavier-Neto 2000 Xavier-Neto et al. 2001 In chick loss of function experiments using dietary deficiency and by the use of RA antagonists have shown anterior- posterior problems and disrupted heart looping (Chazaud et al. 1999 Ghatpande et al. 2000 Hochgreb et al. 2003 Kostetskii et al. 1999 IWP-3 Tsukui et al. 1999 During later on phases of cardiogenesis RA is definitely generated from the epicardium and is important in stimulating proliferation of the ventricular myocardium (Chen et al. IWP-3 2002 Munoz-Chapuli et al. 2002 Stuckmann et al. 2003 Xavier-Neto et al. 2000 Several key questions remain concerning the part of RA in cardiogenesis. First do the variety of tasks ascribed to RA symbolize a common underlying theme such as axis formation or modulation of differentiation? Second of all if the sites of synthesis and degradation of RA are arranged in such a manner that a graded level of RA should be seen in the heart why does a global software of IWP-3 RA save cardiac defects in various models of RA insufficiency (Xavier-Neto et al. 2001 A better understanding of the phylogenetic variations in cardiogenesis and the part of RA signaling in the process will help elucidate underlying mechanisms in heart development (Xavier-Neto et al. 2001 To this end we have endeavored to clarify the part of RA signaling in cardiogenesis. As in additional model systems is definitely expressed near the sino-atrial region of the developing heart IWP-3 and Cyp26 the enzyme primarily responsible for RA degradation is definitely expressed inside a nonoverlapping complementary pattern (Haselbeck et al. 1999 Hollemann et al. 1998 embryos exposed to excessive RA prior to cardiac differentiation have a.