Atoh1 mediated disturbance of neuronal maturation by perinatal hypoxia induces cognitive deficits.

Neurodevelopmental disorders are currently one of the major complications faced by patients with congenital heart disease (CHD). Chronic hypoxia in the prenatal and postnatal preoperative brain may be associated with neurological damage and impaired long-term cognitive function, but the exact mechanisms are unknown. In this study, we find that delayed neuronal migration and impaired synaptic development are attributed to altered Atoh1 under chronic hypoxia. This is due to the fact that excessive Atoh1 facilitates expression of Kif21b, which causes excess in free-state α-tubulin, leading to disrupted microtubule dynamic stability. Furthermore, the delay in neonatal brain maturation induces cognitive disabilities in adult mice. Then, by down-regulating Atoh1 we alleviate the impairment of cell migration and synaptic development, improving the cognitive behavior of mice to some extent. Taken together, our work unveil that Atoh1 may be one of the targets to ameliorate hypoxia-induced neurodevelopmental disabilities and cognitive impairment in CHD.

Loss of circIGF1R Suppresses Cardiomyocytes Proliferation by Sponging miR-362-5p.

Circular RNAs (circRNAs) are generally formed by the back-splicing of precursor mRNA. Increasing evidence implicates the important role of circRNAs in cardiovascular diseases. However, the role of circ-insulin-like growth factor 1 receptor (circIGF1R) in cardiomyocyte (CM) proliferation remains unclear. Here, we investigated the potential role of the circIGF1R in the proliferation of CMs. We found that circIGF1R expression in heart tissues and primary CMs from adult mice was significantly lower than that in neonatal mice at postnatal 1 day (p1). Increased circIGF1R expression was detected in the injured neonatal heart at 0.5 and 1 days post-resection. circIGF1R knockdown significantly decreased the proliferation of primary CMs. Combined prediction software, luciferase reporter gene analysis, and quantitative real time-PCR (qPCR) revealed that circIGF1R interacted with miR-362-5p. A significant increase in miR-362-5p expression was detected in the adult heart compared with that in the neonatal heart. Further, heart injury significantly decreased the expression of miR-362-5p in neonatal mice. Treatment with miR-362-5p mimics significantly suppressed the proliferation of primary CMs, whereas knockdown of miR-362-5p promoted the CMs proliferation. Meanwhile, miR-362-5p silencing can rescue the proliferation inhibition of CMs induced by circIGF1R knockdown. Target prediction and qPCR validation revealed that miR-362-5p significantly inhibited the expression of Phf3 in primary CMs. In addition, decreased Phf3 expression was detected in adult hearts compared with neonatal hearts. Consistently, increased Phf3 expression was detected in injured neonatal hearts compared with that in sham hearts. Knockdown of Phf3 markedly repressed CMs proliferation. Taken together, these findings suggest that circIGF1R might contribute to cardiomyocyte proliferation by promoting Pfh3 expression by sponging miR-362-5p and provide an important experimental basis for the regulation of heart regeneration.