Wnt signaling is a key mediator of Cdx1 expression in vivo.
In the mouse, Cdx1 is essential for normal anteroposterior vertebral patterning through regulation of a subset of Hox genes. Retinoic acid (RA) and certain Wnts have also been implicated in vertebral patterning, although the relationship between these signaling pathways and the regulation of mesodermal Hox gene expression is not fully understood. Prior work has shown that Cdx1 is a direct target of both Wnt and retinoid signaling pathways, and might therefore act to relay these signals to the Hox genes. Wnt and RA are believed to impact on Cdx1 through an atypical RA-response element (RARE) and Lef/Tcf-response elements (LRE), respectively, in the proximal promoter. To address the roles of these regulatory motifs and pathways, we derived mice mutated for the LRE or the LRE plus the RARE. In contrast to RARE-null mutants, which exhibit limited vertebral defects, LRE-null and LRE+RARE-null mutants exhibited vertebral malformations affecting the entire cervical region that closely phenocopied the malformations seen in Cdx1-null mutants. Mutation of the LRE also greatly reduced induction of Cdx1 by RA, demonstrating a requirement for Wnt signaling in the regulation of this gene by retinoids. LRE and LRE+RARE mutants also exhibited vertebral fusions, suggesting a defect in somitogenesis. As Wnt signaling is implicated in somitogenesis upstream of the Notch pathway, it is conceivable that Cdx1 might play a role in this process. However, none of the Notch pathway genes assessed was overtly affected.
Pilon
Nicolas
N
Clinical Research Institute of Montreal, Montreal, Quebec, Canada.
Oh
Karen
K
Sylvestre
Jean-René
JR
Savory
Joanne G A
JG
Lohnes
David
D
D000483:Alleles; D000818:Animals; D019521:Body Patterning / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D005801:Genes, Homeobox; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D017403:In Situ Hybridization; D051379:Mice; D009154:Mutation; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020218:Response Elements; D015398:Signal Transduction; D014212:Tretinoin / Q000494:pharmacology; D051153:Wnt Proteins / Q000378:metabolism*
C491272:Cdx1 protein, mouse; D018398:Homeodomain Proteins; D018168:Receptors, Retinoic Acid; D051153:Wnt Proteins; D014212:Tretinoin