Department of Cardiothoracic Surgery, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China.
Nanjing University, Nanjing, 210008, China.
Commun Biol. 2024 Sep 11;7(1):1121. doi: 10.1038/s42003-024-06846-7.
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.
神经发育障碍是先天性心脏病（CHD）患者目前面临的主要并发症之一。胎儿期和术前围生期的慢性脑缺氧可能与神经损伤和认知功能长期受损有关，但确切的机制尚不清楚。在这项研究中，我们发现慢性缺氧下 Atoh1 的改变导致神经元迁移延迟和突触发育受损。这是因为过多的 Atoh1 促进了 Kif21b 的表达，导致游离状态的α-微管蛋白过多，从而破坏了微管动态稳定性。此外，新生脑成熟的延迟导致成年小鼠认知障碍。然后，通过下调 Atoh1，我们减轻了细胞迁移和突触发育的损伤，在一定程度上改善了小鼠的认知行为。总之，我们的工作揭示了 Atoh1 可能是改善 CHD 中缺氧诱导的神经发育障碍和认知障碍的靶点之一。
