RNA末端转移酶TUT1在神经发育障碍中的作用与机制研究

Autism is a neurodevelopmental disorder commonly accompanied by intellectual disability. Recent studies have uncovered mutations in several hundreds of genes associated with autism, although their functional relevance remains largely unknown. Here we provide evidence to support TUT1 as a causative autism gene. We identify a de novo nonsense mutation in TUT1 by whole-exome sequencing in an autistic child with intellectual disability. Modelling in zebrafish reveals severe defects in the developing brain due to tut1 disruption. Furthermore we show that TUT1 protein sustains stem cell proliferation by maintaining the expression of LIN28, an important regulator of neurogenesis. We recently identified LARP7 as the interacting partner of TUT1 protein. Importantly, the expression pattern of LARP7 in prenatal human brains largely mirrors that of PAX6, TBR2 and YAP1, critical regulators of neural progenitor proliferation. TUT1 was originally shown to function as RNA uridylyltransferase, a notion recently challenged by studies demonstrating TUT1 as poly(A) polymerase. We show that this discrepancy may be explained by different terminal structures of RNA substrates, and the substrate preference of TUT1 is additionally controlled by its interaction with LARP7 protein. Intriguingly, disruptive mutations in LARP7 were causatively linked to intellectual disability recently. Our findings thus reveal a previously unrecognized role of the LARP7-TUT1-LIN28 axis in brain development, and support the notion that dysregulation of neural progenitor proliferation is one of the common neurobiological features underlying autism etiology.

自闭症（autism）和智障（intellectual disability）是两种经常伴随出现的儿童神经发育障碍；有超过75%的自闭症患者同时表现出智障。2014年发布的《中国自闭症儿童发展状况报告》保守估计我国的自闭症/智障患者超过1000万。尽管自闭症和智障具有不同的临床诊断标准，如此高的伴随出现率提示这两种神经发育障碍影响共同的生物学途径。科学界过去5年的研究鉴定了超过500个潜在的自闭症/智障致病关联基因。系统研究这些基因如何导致自闭症/智障发生发展，发现他们所影响的生物学途径和关键蛋白，将为临床干预儿童神经发育障碍提供新思路和手段。本项目以自主发现的自闭症/智障关联基因TUT1为切入点，利用动物模型、干细胞系统和生物化学/分子生物手段从宏观到微观层面探讨TUT1对神经系统发育的影响，以及在神经发育障碍中的作用与机制；并为后续研究其他关联基因的作用机制提供思路和研究平台。

神经发育障碍是一种遗传性或者获得性病因导致的认知和社交能力障碍的疾病。大多数情况下，该疾病的生物学基础尚不清楚。本项目中，我们鉴定并证实了编码双功能RNA末端转移酶TUT1为人类智力障碍/自闭症候补基因。在中国患者队列研究中，我们发现了TUT1的破坏性变异，并进一步证实了TUT1在包含2,000多个自闭症家庭的SFARI数据库中的重要性。一系列功能研究表明，TUT1对于脊椎动物的大脑发育至关重要，并可能通过调节干细胞增殖来实现其对大脑发育的影响。此外，我们发现，TUT1的酶活性受LARP7（致病性智力障碍/自闭症基因）调控。TUT1和LARP7的表达在出生前人脑的神经祖细胞中高度富集，这与神经发生过程中干细胞的功能性作用一致。这些结果与最近的观点相印证，即干细胞增殖/分化失调会导致人类神经发育障碍；此外，以上研究结果也表明这种跨疾病方法可有效地识别人类发育性脑疾病的候选基因。