Developmental expression of retinoic acid receptors (RARs).
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.
PubMed ID: 19471585
PMC ID: PMC2686085
Article link: Nucl Recept Signal.
Genes referenced: act3 cyp26a1 npat rab40b rara rarb rarg rpe rxra rxrb rxrg tbx2 tcf3
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|Figure 1. Expression of murine Rar genes in somite-stage embryos.Adjacent histological sections (planes of section as indicated by arrows on the schemes) from two embryos at the 8 somite (A,D,G) and 14 somite (B,C,E,F,H,I) stages were hybridized with 35S-labelled riboprobes for Rara (A-C), Rarb (D-F) and Rarg (G-I). Following emulsion autoradiography, sections are viewed under dark-field illumination showing the signal grains in white. Bright-field views are shown above for histology. Abbreviations: ce, celomic cavity; fg, foregut; hb, hindbrain; he, heart; hg, hindgut; me, mesoderm (primary mesenchyme); nc, neural crest; nf, neural folds; nt, neural tube; oc, occipital somite; ph, first pharyngeal (mandibular) arch; so, somite; sp, splanchnopleure; st, stomach primordium. From (Ruberte et al., 1991).|
|Figure 2. Early expression features of murine Rarb.A,B: Whole-mount ISH of E8.5 (dorsal view) and E9.5 (profile view) embryos hybridized with a digoxigenin-labelled Rarb probe recognizing all isoforms ('Rarb total', RARβT). Arrows point to the sharp expression boundary in the post-otic hindbrain neuroepithelium (r6/7 boundary). C-E: Comparative ISH with 35S-labelled probes specific for RARβ1/3 and RARβ2/4 isoforms, on serial parasagittal sections of an E9.5 embryo. Abbreviations: ba, first branchial arch; fg, foregut; mg, midgut; ppc, peritoneal-pericardial region; r7, rhombomere 7; sc, spinal cord; st, stomach primordium; str, septum transversum; um, umbilical region. (A,B) from (Serpente et al., 2005). (C-E) from (Mollard et al., 2000).|
|Figure 3. Expression features of murine Rarg.Parasagittal sections of E9.5 (A) and E12.5 (B) embryos; transverse section of an E12.5 embryo (C); detail of the oesophagus (oe) and stomach (st) of an E14.5 fetus (D), arrow pointing to the expression boundary at the limit of the squamous stomachal epithelium. 35S-labelled probes. Other abbreviations: I,II, branchial arches; Br, brain; br, stem bronchus; fl, forelimb bud; fm, frontonasal mesenchyme; hl, hindlimb bud; ma, mandible primordium; nc, nasal precartilage; nt, neural tube; oc, otic capsule; opv, optic vesicle; pv, prevertebra; ri, rib anlage; sk, sclerotome. From (Ruberte et al., 1990).|
|Figure 4. RAR gene and protein expression in the developing brain and eye.(A-D) Comparative ISH of RARα2, RARβ1/3 and RARβ2/4 on neighboring sections of the corpus striatum (lateral ganglionic eminence) of an E13.5 fetal mouse brain. 35S-labelled probes. (E-H) Immunofluorescence detection of RARαT, RARβT and RARγT on serial sections of an E10.5 eye. Abbreviations: cc, cerebral cortex; cs, corpus striatum; L, lens; lv, lateral ventricle; ol, olfactory epithelium; PM, periocular mesenchyme; R, neural retina; RPE, retinal pigmented epithelium; sv, subventricular zone. (A-D) from (Mollard et al., 2000). (E-H) from (Mori et al., 2001).|
|Figure 5. RAR expression in the differentiating limb.Comparative ISH of RARβ1/3, RARβ2/4, RARγ1 and RARγ2 on serial sections through the extremity (footplate) of an E13.5 hindlimb. 35S-labelled probes. Abbreviations: dc, digit precartilaginous condensation; fp, footplate; id, interdigital domain; mg, midgut; mu, muscle; zp, zeugopod (tibia/fibula region). From (Mollard et al., 2000).|
|Figure 6. RAR expression in differentiating organs.(A-C) Comparative ISH of Rarb and Rarg on neighboring sections of the lung of an E14.5 mouse fetus. (D-G) Details of Rarb expression in abdominal organs at E12.5, and in the developing kidney at E14.5. 35S-labelled probes. Abbreviations: ad, adrenal gland; br, bronchus; d, diaphragm; g, gut; l, liver; m, metanephros; o, oesophagus; p, pancreas; ps, pyloric region of the stomach; t, metanephric tubules. From (Dolle et al., 1990).|