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FolR1 gene ablation-induced changes in gene expression in mouse conotrucus tissue and developing heart

ABSTRACT: Defective function of FolR1 in mice results in inadequate transport, accumulation, or metabolism of folate during cardiovascular morphogenesis. We have observed cardiovascular abnormalities including outflow track defects and aortic arch artery defects in these genetically compromised mice. In order to investigate the mechanisms underlying the failure to complete cardiac development in the transgenic mouse model, we studied gene expression difference between FolR1 knockout embryos and normal embryos during outflow track septation (GD11:12, GSM78976 ... GSM78987), and studied gene expression difference between FolR1 knockout embryos and normal embryos during embryonic heart development(GD9:00 and GD10:00, GSM79024 ... GSM79035). Keywords: gene ablation response

ORGANISM(S): Mus musculus

PROVIDER: GSE3487 | GEO | 2006/02/20

SECONDARY ACCESSION(S): PRJNA93307

REPOSITORIES: GEO

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Project description:Retinoic acid (RA), the bioactive derivative of vitamin A, is essential for vertebrate heart development. Both excess and reduced RA signaling lead to cardiovascular malformations, particularly affecting the cardiac outflow tract (OFT). The cellular mechanisms underlying the effects of RA signaling during OFT morphogenesis are not fully understood. To address this question, we used transient maternal RA supplementation to rescue the early lethality resulting from inactivation of the murine retinaldehyde dehydrogenase 2 (Raldh2) gene. By embryonic day 13.5, Raldh2-/- hearts exhibited OFT septation defects. Although cardiac neural crest cells (cNCC) were present in OFT cushions of Raldh2-/- mutant embryos, we observed that cNCC were ectopically located in the peripheral region of the endocardial cushions, closer to the myocardium rather than immediately subjacent to the endocardium. Mislocated cNCC were aligned in parallel instead of perpendicular arrays to the endocardial surface within the proximal OFT. Supernumerary mesenchyme was generated both in and ex vivo within the cushions by Raldh2-/- mutant endocardium and found in place of the cNCC in a subendocardial, medial position. Although mislocated and misoriented, mutant cNCC resembled wildtype cells in their compaction density and individually elongated shape. Our data show that RA signaling acts on cNCC orientation relative to the septation plane and position within OFT cushions during septation process. Transcriptomic analysis and pathway-specific readout suggest that up-regulation of the Bmp pathway may be responsible for increased endothelial-to-mesenchymal transition, leading thereby to displacement of cNCC. E10.5 stage embryonic mouse outflow tracts were microdissected. Four pools of four outflow tracts were established for wildtype (WT) and mutant (Raldh2-/-) embryos derived from dams whose food had been supplemented with all-trans-RA (Sigma) directly mixed into powdered food at 0.1 mg/g food and offered between E7.5 and E8.5. Total RNA was extracted using Macherey-Nagel NucleoSpinÂ® RNA columns without on-column DNase digestion.

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FolR1 gene ablation-induced changes in gene expression in mouse conotrucus tissue and developing heart

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