Abstract
Sorting nexin 17 (SNX17), a member of sorting nexin (SNX) family, acts as a modulator for endocytic recycling of membrane proteins. Results from our previous study demonstrated the embryonic lethality of homozygous defect of SNX17. In this study, we investigated the role of SNX17 in rat fetal development. Specifically, we analyzed patterns of SNX17 messenger RNA (mRNA) expression in multiple rat tissues and found high expression in the cardiac outflow tract (OFT). This expression was gradually elevated during the cardiac OFT morphogenesis. Homozygous deletion of the SNX17 gene in rats resulted in mid-gestational embryonic lethality, which was accompanied by congenital heart defects, including the double-outlet right ventricle and atrioventricular and ventricular septal defects, whereas heterozygotes exhibited normal fetal development. Moreover, we found normal migration distance and the number of cardiac neural crest cells during the OFT morphogenesis. Although cellular proliferation in the cardiac OFT endocardial cushion was not affected, cellular apoptosis was significantly suppressed. Transcriptomic profiles and quantitative real-time PCR data in the cardiac OFT showed that SNX17 deletion resulted in abnormal expression of genes associated with cardiac development. Overall, these findings suggest that SNX17 plays a crucial role in cardiac development.
Highlights
The heart is the first functional organ formed during vertebrate embryogenesis [1]
Sorting nexin 17 (SNX17) was upregulated during the cardiac outflow tract (OFT) morphogenesis from E12.5 to E14.5 (Figure 1D), highlighting a close relationship between SNX17 and the cardiac OFT remodeling
SNX17 was expressed in other regions during subsequent stages, it was upregulated in the OFT region at E12.5 relative to the other cardiac regions (Figures 1C,F)
Summary
The heart is the first functional organ formed during vertebrate embryogenesis [1]. Cardiac development mainly consists of four stages, namely, the cardiac crescent, heart tube, cardiac looping, and formation of the four-chambered heart, and involves coordination of multicell or multi-signaling interactions [2]. Abnormal heart development has been associated with development of congenital heart defects (CHDs), which account for a third of all the major congenital anomalies [3]. The highest birth prevalence of CHDs, 9.3 per 1,000 live births, has been reported in Asia [4]. Malformations of the cardiac outflow tract (OFT) and the great arteries account for ∼30% of all the CHDs [5].
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