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A Cdx4-Sall4 regulatory module controls the transition from mesoderm formation to embryonic hematopoiesis

ABSTRACT: Deletion of caudal/cdx genes alters hox gene expression and causes defects in posterior tissues and hematopoiesis. Yet, the defects in hox gene expression only partially explain these phenotypes. To gain deeper insight into Cdx4 function, we performed ChIP-seq combined with gene expression profiling in zebrafish, and identified the transcription factor spalt-like 4 (sall4) as a Cdx4 target. ChIP-seq revealed that Sall4 bound to its own gene locus and the cdx4 locus. Expression profiling showed that Cdx4 and Sall4 co-regulate genes such as hox, scl, and lmo2 that initiate hematopoiesis. Combined cdx4/sall4 gene knock-down impairs erythropoiesis, and overexpression of the Cdx4 and Sall4 target genes scl and lmo2 together rescued the erythroid program. These findings suggest that auto- and cross- regulation of Cdx4 and Sall4 establish a stable molecular circuit in mesoderm that facilitates the activation of the blood-specific program as development proceeds.

ORGANISM(S): Danio rerio

PROVIDER: GSE48254 | GEO | 2013/12/02

SECONDARY ACCESSION(S): PRJNA209381

REPOSITORIES: GEO

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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.

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A Cdx4-Sall4 regulatory module controls the transition from mesoderm formation to embryonic hematopoiesis

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