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doi: 10.1242/10.1242/dev.00428

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Retinoic acid-induced developmental defects are mediated by RARß/RXR heterodimers in the pharyngeal endoderm

Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, Collège de France, BP 10142, 67404 Illkirch Cedex, CU de Strasbourg, France

View larger version (120K): [in a new window]   Fig. 1. Effects of the panRAR-selective agonist TTNPB on branchial arch development. Morphology of vehicle-treated (A) and TTNPB-treated (B) wild-type embryos after 48 hours in culture. B1-B3, branchial arches 1 to 3, respectively; B1-2, fused first and second branchial arches; H, heart; O, otocyst. Arrowhead indicates the first branchial cleft.

View larger version (120K): [in a new window]   Fig. 2. Effects on branchial arch development of the RARß agonist BMS453. External (A-D) and histological (E,F) aspects of the pharyngeal region of wild-type embryos after 48 hours in culture without retinoid (vehicle; A,C,E) or in the presence of the RARß-selective agonist (B,D,F). Embryos in C and D were injected with ink. Frontal histological sections (E,F) were obtained from comparable levels of the embryos. A1-A3, aortic arches 1 to 3, respectively; A1-2 fused first and second aortic arches; B1-B3, branchial arches 1 to 3, respectively; B1-2, fused first and second branchial arches; D, dorsal aorta; H, heart; P1, first pharyngeal pouch. White arrowhead (A) indicates the first branchial cleft. Scale bar in F: 200 µm in E,F.

View larger version (108K): [in a new window]   Fig. 4. The RAR-selective (BMS753) and the RAR-selective (BMS961) agonists, induce ectopic expression of the Rare-hsp68-lacZ transgene in the frontonasal mass and tail, respectively, without altering branchial arch development. Ventral views (A,D,G) of wild-type embryos, and details of their pharyngeal (B,E,H) and caudal (C,F,I) regions, after 48 hours in culture either without retinoid (vehicle) or in the presence of isotype-selective RAR agonists. B1 and B2, branchial arches 1 and 2, respectively; F, frontonasal process; H, heart. Arrowheads indicate the first branchial cleft and red arrows point to the tips of the tails.

View larger version (91K): [in a new window]   Fig. 3. Effects on branchial pouch development of the RARß agonist BMS453. Embryos were hybridized with a Pax1 antisense probe after 12, 24 and 48 hours in culture. (A,B) external views. (C-F) Embryos cut sagittally into halves; the medial side of the right half is displayed. (G-L) Ventral views of flat mounts from isolated pharyngeal endoderm. B1-B3, branchial arches 1 to 3, respectively; B1-2, fused first and second branchial arches; H, heart; O, otocyst; P1-P3, pharyngeal pouches 1 to 3, respectively; P1-2, fused first and second pharyngeal pouches; S, somites. A-F and G-L are displayed at the same magnification.

View larger version (101K): [in a new window]   Fig. 5. Rarb-null embryos are resistant to BMS453-induced teratogenic effects. External views (A,B) and frontal histological sections (C,D) of the branchial arches of Rarb-null embryos after 48 hours in culture either without retinoid (vehicle) or in the presence of BMS453. A1-A3 and B1-B3, aortic arches and branchial arches 1 to 3, respectively; P1, first pharyngeal pouch. Scale bar in D: 200 µm for C,D.

View larger version (57K): [in a new window]   Fig. 6. BMS453-induced branchial arch defects and ectopic activation of the RARß2 promoter are prevented by the panRAR-selective antagonist BMS493. Embryos carrying the Rarb2-lacZ transgene in a wild-type genetic background were cultured for 48 hours. B1-B3, branchial arches 1 to 3, respectively; B1-2, fused first and second branchial arches; O, otocyst; R7, rhombomere 7; R3/R4, boundary between rhombomeres 3 and 4. Arrowheads indicate the first branchial cleft.

View larger version (87K): [in a new window]   Fig. 7. Expression of lacZ in vehicle-treated and BMS453-treated embryos carrying the Rare-hsp68-lacZ transgene in a wild-type (WT; A,H) and in an Rarb-null (Rarb–/–; I) genetic background, after 24 hours (A-D,G-I) or 30 hours (E,F) in culture. (A,B) Dorsal views of intact embryos. (C,D) Embryos cut sagittally into halves; the medial side of the right half is displayed. (E,F) Frontal histological sections through the pharynx. (G-I) Lateral views of intact embryos. Brackets (G-I) indicate the putative localization of migrating NCCs destined to the second BA. B1-B2 and M1-M2, branchial arches 1 and 2, and their mesenchyme, respectively; B1-2 and M1-2, fused first and second branchial arches and their mesenchyme, respectively; aE and pE, anterior and posterior regions of the pharyngeal endoderm, respectively; EC, ectoderm; F, frontonasal process; H, heart; O, otocyst; P1, first pharyngeal pouch; R2-R5, rhombomeres 2 to 5, respectively. Scale bar in F: 100 µm for E,F.

View larger version (105K): [in a new window]   Fig. 8. Expression of Hoxa1 and Hoxb1 in vehicle-treated and BMS453-treated wild-type embryos after 24 hours in culture. All embryos were cut sagittally into halves and the medial side of the right half is displayed. aE and pE, anterior and posterior parts of the pharyngeal endoderm, respectively; F, frontonasal process; R3 and R4, rhombomeres 3 and 4, respectively.

View larger version (84K): [in a new window]   Fig. 9. Distribution of mRARß transcripts in vehicle-treated and BMS453-treated wild-type embryos after 24 hours in culture. (A,B) Frontal histological sections through the rhombencephalon. (C,D) Embryos hybridized in toto with the mRARß probe cut sagittally into halves; the left medial side is displayed. aE and pE, anterior and posterior parts of the pharyngeal endoderm, respectively; F, frontonasal process; H, heart; O, otocyst; R4-R7, rhombomeres 4 to 7, respectively. Scale bar in B: 150 µm for A,B.

View larger version (77K): [in a new window]   Fig. 10. Synergistic effects of the RARß agonist BMS453 and of the panRXR-selective agonist BMS649. Frontal histological sections are from comparable levels of wild-type embryos after 48 hours in culture. A1-A3, aortic arches 1 to 3, respectively; A1-A2 fused first and second aortic arches; P1, first pharyngeal pouch. Arrowhead indicates the first branchial cleft. Scale bar in A: 200 µm for A-C.

View larger version (110K): [in a new window]   Fig. 11. Treatment with the RARß agonist BMS453 decreases RA signalling in the frontonasal process and tail. External views (A-C,G-I) and frontal histological sections (D-F) of embryos carrying the Rare-hsp68-lacZ transgene in a wild-type genetic background. Transgenic embryos were cultured for 24 hours (G-I) or 30 hours (A-F) in the presence of vehicle (A,D,G), BMS453 (B,E,H) and the panRAR-selective agonist TTNPB (C,F,I). aE, anterior part of the pharyngeal endoderm; F, frontonasal process; FO, forebrain; D, mesonephric duct; G, foregut; H, heart; M, mesenchyme of the frontonasal process; OV, optic vesicle; SC, spinal cord; T, tail. Scale bar in F: 400 µm for D-F.

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