title: Concerted involvement of Cdx/Hox genes and Wnt signaling in morphogenesis of the caudal neural tube and cloacal derivatives from the posterior growth zone.
abstract: Decrease in Cdx dosage in an allelic series of mouse Cdx mutants leads to progressively more severe posterior vertebral defects. These defects are corrected by posterior gain of function of the Wnt effector Lef1. Precocious expression of Hox paralogous 13 genes also induces vertebral axis truncation by antagonizing Cdx function. We report here that the phenotypic similarity also applies to patterning of the caudal neural tube and uro-rectal tracts in Cdx and Wnt3a mutants, and in embryos precociously expressing Hox13 genes. Cdx2 inactivation after placentation leads to posterior defects, including incomplete uro-rectal septation. Compound mutants carrying one active Cdx2 allele in the Cdx4-null background (Cdx2/4), transgenic embryos precociously expressing Hox13 genes and a novel Wnt3a hypomorph mutant all manifest a comparable phenotype with similar uro-rectal defects. Phenotype and transcriptome analysis in early Cdx mutants, genetic rescue experiments and gene expression studies lead us to propose that Cdx transcription factors act via Wnt signaling during the laying down of uro-rectal mesoderm, and that they are operative in an early phase of these events, at the site of tissue progenitors in the posterior growth zone of the embryo. Cdx and Wnt mutations and premature Hox13 expression also cause similar neural dysmorphology, including ectopic neural structures that sometimes lead to neural tube splitting at caudal axial levels. These findings involve the Cdx genes, canonical Wnt signaling and the temporal control of posterior Hox gene expression in posterior morphogenesis in the different embryonic germ layers. They shed a new light on the etiology of the caudal dysplasia or caudal regression range of human congenital defects.
authors.affiliation: Hubrecht Institute, Developmental Biology and Stem Cell Research, Utrecht, The Netherlands.
authors.forename: Cesca
authors.initials: C
authors.lastname: van de Ven
authors.forename: Monika
authors.initials: M
authors.lastname: Bialecka
authors.forename: Roel
authors.initials: R
authors.lastname: Neijts
authors.forename: Teddy
authors.initials: T
authors.lastname: Young
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Rowland
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Stringer
authors.forename: Carina
authors.initials: C
authors.lastname: Van Rooijen
authors.forename: Frits
authors.initials: F
authors.lastname: Meijlink
authors.forename: Ana
authors.initials: A
authors.lastname: Nóvoa
authors.forename: Jean-Noel
authors.initials: JN
authors.lastname: Freund
authors.forename: Moises
authors.initials: M
authors.lastname: Mallo
authors.forename: Felix
authors.initials: F
authors.lastname: Beck
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Deschamps
mesh_terms: D000818:Animals; D000071616:CDX2 Transcription Factor; D048430:Cell Shape; D004622:Embryo, Mammalian / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054259:Neural Tube / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein
chemical_list: D000071616:CDX2 Transcription Factor; C487514:Cdx2 protein, mouse; C084563:Cdx4 protein, mouse; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; C465570:Shh protein, mouse; D014157:Transcription Factors; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D014212:Tretinoin