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The Role of Sorting Nexin 17 in Cardiac Development

ABSTRACT: Homozygous deletion of the SNX17 gene in rats resulted in mid-gestational embryonic lethality which was accompanied by congenital heart defects, including in the double-outlet right ventricle, atrioventricular and ventricular septal defects. To elucidate the potential mechanisms underlying development of cardiac OFT defects induced by SNX17 knockout, we performed RNA-seq analysis in cardiac outflow tract (OFT) tissues isolated from WT and HO embryos at E13.5. A total of 262 differentially expressed genes (DEGs) were identified between WT and HO samples, of which 94 and 168 were up-regulated and down-regulated, respectively. Analysis of biological functions of the DEGs, via Gene Ontology (GO), revealed that the up-regulated genes were mainly involved in heart development, and negative regulation of the intrinsic apoptotic pathway, while the down-regulated DEGs were associated with cell adhesion, extracellular organization, and negative regulation of the Wnt signaling pathway.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE186706 | GEO | 2021/10/30

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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The Role of Sorting Nexin 17 in Cardiac Development

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