Project description: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 urorectal 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 signalling during the laying down of urorectal 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 sometimes leading to neural tube splitting at caudal axial levels. These findings involve the Cdx genes, canonical Wnt signalling, 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. We used dissected Cdx2 null mutant versus wild type embryos at the 4/5 somite and 7/8 somite stage. RNA was isolated from the posterior part of the embryos (20 embryos of each genotype and stage), dissected at the same axial levels by using the last somite boundary and the base of the allantois as landmarks. Differentially labelled cRNA from the Cdx2 and control embryos were hybridized on 4X44K Agilent Whole Mouse Genome dual colour Microarrays (G4122F) in two dye swap experiments and two technical replicates, resulting in eight individual arrays.

Project description:The vertebrate main-body axis is laid down during embryonic stages in an anterior-to-posterior (head-to-tail) direction, driven and supplied by posteriorly located progenitors. For the vertebral column, the process of axial progenitor cell expansion that drives axis elongation, and the process of segmentation which allocates these progenitors into repeating vertebral units, occurs seemingly uninterrupted from the first to the last vertebra. Nonetheless, there is clear developmental and evolutionary support for two discrete modules controlling processes within different axial regions: a trunk module and a tail module. The secreted signal Gdf11 has been identified as a principal regulator of timing the trunk-to-tail (T-to-T) transition, but has pleiotropic effects across much of the main body axis, highlighting the need to reveal intrinsic regulatory networks that function to exclusively control one or the other module. Here, we identify Nuclear receptor subfamily 6 group A member 1 (Nr6a1) as a master regulator of elongation, patterning and lineage allocation specifically within the trunk region of the mouse. Both gain- and loss-of-function in vivo analysis revealed that the precise level of Nr6a1 acts as a rheostat, expanding or contracting vertebral number of the trunk region autonomously from other axial regions. Moreover, the timely clearance of Nr6a1 observed at the T-to-T transition was essential in allowing the tail module to operate correctly. In parallel with these effects on vertebral number, we show that Nr6a1 controls the timely progression of global Hox signatures within axial progenitors, preventing the precocious expression of multiple posterior Hox genes as the trunk is being laid down and thus reinforcing that patterning and elongation are coordinated. Finally, our data supports a crucial role for Nr6a1 in regulating gene regulatory networks that guide cell lineage choice of axial progenitors between neural and mesodermal fate. Collectively, our data reveals an axially-restricted role for Nr6a1 in all major cellular and tissue-level events required for vertebral column formation, supporting the view that modulation of Nr6a1 expression level or function may underpin evolutionary changes in axial formulae that exclusively alter the trunk region.

Dataset Information

Transcription profiling of mouse Cdx2+/-Cdx4-/- mutant embryos versus wild type embryos at the 13 somite stage

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