mechanism or through an intermediary; these mechanisms are not necessarily exclusive. In this regard, we have found that Cdx1 may serve as such an intermediary. Cdx1 encodes a homeobox transcription factor that is crucial for normal somitic expression of several Hox genes, and is regulated by retinoid signalling in vivo and in vitro likely through an atypical RARE in the proximal promoter. In order to more fully understand the relationship between retinoid signalling, Cdx1 expression and AP patterning, we have derived mice in which the RARE has been functionally inactivated. These RARE-null mutants exhibit reduced expression of Cdx1 at all stages examined, vertebral homeotic transformations and altered Hox gene expression which correlates with certain of the defects seen in Cdx1-null offspring. These findings are consistent with a pivotal role for retinoid signalling in governing a subset of expression of Cdx1 crucial for normal vertebral patterning. Research article 6556 retinoic acid (RA) plays a crucial role (Marshall et al., 1996). RA can induce Hox genes in embryocarcinoma cells in a manner reminiscent of the normal temporal activation of Hox expression, with 3′ genes from a given cluster responding earlier, and to lower concentrations of RA, than more 5′ members (Boncinelli et al., 1991;Simeone et al., 1990). In vivo, administration of exogenous RA to mouse embryos between E7.5 and E8.5 typically results in anteriorization of a number of Hox genes in a manner that correlates with posterior vertebral homeotic transformations (Conlon and Rossant, 1992;Kessel, 1992;Kessel and Gruss, 1991). Similar effects are also elicited by RA on expression of Hox genes in the CNS and concomitant perturbation of rhombomere patterning (Gavalas and Krumlauf, 2000;Gould et al., 1998;Marshall et al., 1992).The RA signal is transduced by the RA receptors (RARα, RARβ, RARγ and their isoforms). RARs belong to the family of ligand-inducible nuclear receptors and regulate expression of retinoid target genes as heterodimers with a retinoid X receptor (RXRα, RXRβ, RXRγ) partner. RXR-RAR heterodimers function by binding to cis-acting regulatory sequences (RAREs) present in the promoter region of target genes (Chambon, 1996;Mangelsdorf et al., 1995). Consensus RAREs have been described which consist of direct repeats (DR) of the sequence PuG(G/T)TCA with two or five nucleotides intervening the repeats (a DR2 or a DR5 element, respectively). RAREs are, however, highly polymorphic, and a number of variant motifs have been described (Huang et al., 2002;Glass, 1996). Retinoid signaling is also tightly controlled by the opposing actions of RALDH2, which is essential for the generation of most embryonic RA, and CYP26 members, which catabolizes RA (Swindell et al., 1999;Sakai et al., 2001; Abu-Abed et al., 1998;MacLean et al., 2001;Perlmann, 2002).A role for endogenous retinoid signaling in affecting Hox expression and AP patterning is supported by numerous studies (Gavalas et al., 1998;Huang et al., 1998;Zhang et al., 1997). Vertebral homeos...