Developmental expression of retinoic acid receptors (RARs)

Abstract

Here, I review the developmental expression features of genes encoding the retinoic acid receptors (RARs) and the 'retinoid X' or rexinoid receptors (RXRs). The first detailed expression studies were performed in the mouse over two decades ago, following the cloning of the murine Rar genes. These studies revealed complex expression features at all stages of post-implantation development, one receptor gene (Rara) showing widespread expression, the two others (Rarb and Rarg) with highly regionalized and/or cell type-specific expression in both neural and non-neural tissues. Rxr genes also have either widespread (Rxra, Rxrb), or highly-restricted (Rxrg) expression patterns. Studies performed in zebrafish and Xenopus demonstrated expression of Rar and Rxr genes (both maternal and zygotic), at early pre-gastrulation stages. The eventual characterization of specific enzymes involved in the synthesis of retinoic acid (retinol/retinaldehyde dehydrogenases), or the triggering of its catabolism (CYP26 cytochrome P450s), all of them showing differential expression patterns, led to a clearer understanding of the phenomenons regulated by retinoic acid signaling during development. Functional studies involving targeted gene disruptions in the mouse, and additional approaches such as dominant negative receptor expression in other models, have pinpointed the specific, versus partly redundant, roles of the RARs and RXRs in many developing organ systems. These pleiotropic roles are summarized hereafter in relationship to the receptors' expression patterns. IntroductionThe expression patterns of RARs and RXRs have been studied in various species. Initial studies, published shortly after the cloning of RARs and RXRs, have been performed on mouse embryos [Dolle et al., 1989;Dolle et al., 1990;Ruberte et al., 1991;Ruberte et al., 1990]. Reports on other species have often focused on early developmental stages (e.g., Tallafuss et al., 2006] for recent reports on zebrafish rar and rxr gene expression), or on specific organ systems. In a few instances, expression of specific Rar isoforms has been studied [Koide et al., 2001;Mollard et al., 2000;Smith, 1994]. Most studies have analyzed the Rar and Rxr expression patterns at the mRNA level, using in situ hybridization (ISH) and occasionally RT-PCR (e.g., [Ulven et al., 2000]), but there are some reports of RAR/RXR protein distributions analyzed by immunohistochemistry (e.g., [Mori et al., 2001]). Unless otherwise mentioned, the data reviewed hereafter are mRNA expression data. As a general trend, three of the retinoid receptors (RARα, RXRα and RXRβ) have ubiquitous, or quite widespread, expression patterns, with the others (RARβ, RARγ and RXRγ) showing complex, tissue-specific expression. Here, I review the expression features of the Rar and Rxr genes during successive steps of early embryonic development, and for later stages in the various differentiating organ systems. These expression features (see Table 1 for a summary) are discussed in relationship with functional data and current ...

Retinoic acid receptors exhibit cell‐autonomous functions in cranial neural crest cells

“…First, conventional germline RAR compound null mutants display a broad spectrum of abnormalities affecting a variety of organs constituted by cells of multiple origins. Second, RARs exhibit widespread and rapidly changing expression patterns in the developing embryo (Dollé, 2009), and RA is a secreted molecule which can act in a paracrine manner (Matt et al, 2005(Matt et al, , 2008Duester, 2008;Niederreither and Dollé, 2008). To overcome these difficulties and to gain insights into the functions of RA, it was necessary to produce and analyze mice in which RARs were specifically ablated in NCC.…”

“…The effects of RA on embryonic development are mediated by heterodimers between RA receptor (RAR) isotypes (RARa, b, and c) that are widely expressed in the embryo (Mollard et al, 2000;Dollé, 2009) and rexinoid receptors (RXRs; Chambon, 1996;Mark et al, 2009). The requirement of RARs for pattern formation, differentiation, proliferation, and apoptosis during organogenesis has been investigated through generation and analysis of Rar-null mouse models (Mark et al, 2009).…”

Resveratrol Prevents Impairment in Activation of Retinoic Acid Receptors and MAP Kinases in the Embryos of a Rodent Model of Diabetic Embryopathy

“…14 The effects of RA are mediated by both RARs and RXRs. 26 The effect of diabetes on RARs during embryonic development was studied by analyzing the expression of different isoforms of RARs in E12 embryonic cranial neural tube regions (by IHC, Figure 1A) as well as in whole embryo lysates (by Western blot, Figure 1B and C). Twelve-day-old embryos were selected, as this is the age where rat organogenesis is near completion and similar diabetic embryos at this age have been characterized in our previous work.…”

A novel method for retinoic acid administration reveals differential and dose‐dependent downregulation of Fgf3 in the developing inner ear and anterior CNS

“…The effects of RA signaling are spatially and temporally restricted within the embryo through multiple mechanisms such as sequestering the ligand, or regulating the expression of RA biosynthetic enzymes (Duester, 2008) and/or receptors (Dolle, 2009). Indeed the dynamic expression of RARs/RXRs (Dolle, 2009) suggests multiple functions in development, and this was borne out following extensive mutational analyses in the mouse that revealed roles in the development of multiple organ systems, including the developing nervous system, as well as in patterning and growth of the embryo (reviewed in Mark et al, 2009).…”

“…Indeed the dynamic expression of RARs/RXRs (Dolle, 2009) suggests multiple functions in development, and this was borne out following extensive mutational analyses in the mouse that revealed roles in the development of multiple organ systems, including the developing nervous system, as well as in patterning and growth of the embryo (reviewed in Mark et al, 2009). However, the presence of multiple isoforms for the different receptors, and the subsequent functional redundancy exhibited in mutant analysis, suggest that some roles in development still remain undiscovered.…”