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doi: 10.1242/10.1242/dev.00357

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Developing with lethal RA levels: genetic ablation of Rarg can restore the viability of mice lacking Cyp26a1

¹ Cancer Research Labs, Queen's University, Kingston, ON K7L 3N6, Canada
² Institut de Génétique et de Biologie Moléculaire et Cellulaire, Collège de France, BP 163-67404 Illkirch Cedex, CU de Strasbourg, France

View larger version (61K): [in a new window]   Fig. 1. Cyp26a1, Rarg and Raldh2 expression in wild-type and mutant embryos. Comparative views of E9.0 wild-type (WT) embryos, after hybridization with Cyp26a1 (A,B) and Rarg (C,D) riboprobes. Profile views (A,C) and detail of the caudal region (B,D). Note the differential extent of both types of transcripts, Rarg extending more rostrally than Cyp26a1 in both mesodermal (me) and neurectodermal (ne) tissues. (E,F) Rarg transcript distribution in E9.0 wild-type (E) and Cyp26a1-/- (F) embryos. Although the overall Rarg expression level may be decreased (e.g. in the first branchial arches, b1), its spatial distribution does not appear to be altered in the mutant. (G,H) Raldh2 exhibits comparable transcript distributions in E8.0 wild-type (G) and Rarg-/- (H) embryos. b1, first branchial arch; ht, heart; so, somites; tb, tail bud.

View larger version (58K): [in a new window]   Fig. 2. A Rarg-null mutant background rescues the Cyp26a1-null mutant caudal phenotype. In comparison to a wild-type littermate (A, left), two 10-day-old A1-/--/- double mutants (A, right) show kinked and/or shortened tails. Compared with a wild-type skeleton (B) at E18.5, an A1-/--/- (C) skeleton reveals that the tail vertebrae have a normal morphology, although tail development is reduced by approximately four vertebral condensations. The wild-type skeleton (D) exhibits six lumbar (L1-L6; L1 not shown), three fused sacral (S1-S3) and caudal tail (tl) vertebrae. The ilium (il) articulates with S1 and the pelvic bone (pb), which articulates with the hindlimbs. While the skeleton of the A1-/--/- mutant (E) is comparable with that of the wild-type animal, the A1-/- (F) and A1-/-+/- (G) mutants develop abnormally; both skeletons show deformed and abnormally fused lumbar vertebrae (L*), with the A1-/- mutant being more severely affected. Furthermore, in the A1-/-+/- mutant, the malformed pelvic bone (pb*) is connected to abnormally twisted hindlimbs and only six rudimentary caudal vertebrae contribute to the tail (tl*). The A1-/- mutant exhibits a similarly deformed pelvic bone and twisted hindlimbs, as well as a more severe caudal truncation (ct), developing only three sacral rudiments.

View larger version (84K): [in a new window]   Fig. 3. A Rarg-null mutant background rescues a subset of the Cyp26a1-/- cervical vertebral abnormalities. In wild-type skeletons (A), the first cervical vertebra (C1 or atlas) develops a thick neural arch and an anterior arch (AAA); anterior tuberculi (*) distinguish C6. Thoracic (T) vertebrae harbor ribs (see r1 on T1), the first seven of which articulate with the sternum. T2 vertebrae also develop a prominent dorsal spinous process (arrowhead). The A1-/- mutant skeleton (B) shows several posterior homeotic transformations (see Results), including C5 to C6 (C5*), C7 to T1 (C7*) and T1 to T2 (*). In addition, the A1-/- mutant exhibits fusion between the exoccipital bone (eo) and the neural arch of C1 (C1*), an abnormal AAA (AAA*) and bifidus of C2 (C2a* and C2b*). Whereas posterior homeotic transformations are evident in the A1-/--/- mutant (C), including C5 to C6 (C5*), C7 to T1 (C7*) and T1 to T2 (*) transformations, C1 and C2 develop normally. In the A1-/-+/- mutant (D), C7 exhibits a posterior transformation (C7*); also, the neural arch of C1 and the exoccipital bone (eo) are fused.

View larger version (123K): [in a new window]   Fig. 4. Rescue of Brachyury expression in A1-/--/- double mutant embryos. Brachyury expression patterns in the wild-type (A) and A1-/--/- (B) embryos are comparable, showing strong expression in the tail bud (tb) nascent mesoderm and neuroepithelium, as well as the notochord (nc). A1-/-+/- (C) and A1-/- (D) mutants show eversion and twisting of tissues caudal to the posterior neuropore (PNP, arrowhead). Brachyury expression is severely downregulated in the A1-/- mutant tail bud (tb*), while notochord labeling stops abruptly at the level of the PNP (arrowhead).

View larger version (71K): [in a new window]   Fig. 5. Fgf8 and Hnf3b expression patterns are rescued in the tail bud and hindgut of A1-/--/- mutants. Fgf8 is normally (A) expressed in the midbrain-hindbrain junction (white asterisk), maxillary (mx) and mandibular (md) components of the first branchial arch, otic vesicle (ov), commissural plate (cp), heart (ht) and associated vasculature, hindgut (hg), and tail bud (tb) nascent mesoderm. (D) Hnf3b expression is specific of the midbrain (mb), notochord (nc), foregut (fg) and hindgut (hg). In the A1-/- mutant (B), Fgf8 hindgut labeling (hg*) stops at the level of the posterior neuropore (PNP, arrowhead) and expression is down-regulated in the nascent mesoderm of the malformed, twisted tail bud tissues (tb*; see inset). Although Hnf3b notochord labeling persists in the everted tail bud tissues of the A1-/- mutant (E, inset), hindgut labeling ends at the level of the PNP (arrowhead). A1-/--/- double-mutants show normal Fgf8 and Hnf3b patterns of expression (C and F, respectively). aer, apical ectodermal ridge.

View larger version (71K): [in a new window]   Fig. 6. Cdx4 and Hoxd11 expression patterns are downregulated in the tail bud of A1-/- mutants, but are restored in A1-/--/- mutants. Cdx4 is expressed in a graded anteroposterior manner along the tail bud mesoderm (tb), hindgut (hg) and neuroepithelium (ne) of the wild-type embryo (A). Hoxd11 shows prominent expression in tail bud (tb) mesoderm and neuroepithelium of the wild-type (D) embryo. In A1-/- mutants (B) Cdx4 expression is downregulated in the tail bud (tb*) mesoderm, neuroepithelium and hindgut (arrowhead indicates posterior neuropore). A1-/- embryos (E) also show downregulation of Hoxd11 expression in the tail bud (arrowhead indicates last fully formed somite). A1-/--/- mutants exhibit normal Cdx4 (C) and Hoxd11 (F) expression, although, in comparison with the wild-type embryo (D inset), Hoxd11 transcripts extend more rostrally along the ventral mesoderm (vm) (F, inset).

View larger version (18K): [in a new window]   Fig. 7. RAR mediates ectopic RA signaling in the tail bud, a genetic model. See Discussion for rationale. Brachyury is thought to maintain Tbx6 expression (1) (Yamaguchi et al., 1999). Based on studies in Xenopus, FGF8 may play a role in regulating Cdx expression patterns (2).

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