Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
Department of Mathematics, University of British Columbia, Vancouver, BC V6T 1Z2, Canada.
Genetics. 2022 Jul 30;221(4). doi: 10.1093/genetics/iyac094.
Mutations in FMR1 are the most common heritable cause of autism spectrum disorder. FMR1 encodes an RNA-binding protein, FMRP, which binds to long, autism-relevant transcripts and is essential for normal neuronal and ovarian development. In contrast to the prevailing model that FMRP acts to block translation elongation, we previously found that FMRP activates the translation initiation of large proteins in Drosophila oocytes. We now provide evidence that FMRP-dependent translation is conserved and occurs in the mammalian brain. Our comparisons of the mammalian cortex and Drosophila oocyte ribosome profiling data show that translation of FMRP-bound mRNAs decreases to a similar magnitude in FMRP-deficient tissues from both species. The steady-state levels of several FMRP targets were reduced in the Fmr1 KO mouse cortex, including a ∼50% reduction of Auts2, a gene implicated in an autosomal dominant autism spectrum disorder. To distinguish between effects on elongation and initiation, we used a novel metric to detect the rate-limiting ribosome stalling. We found no evidence that FMRP target protein production is governed by translation elongation rates. FMRP translational activation of large proteins may be critical for normal human development, as more than 20 FMRP targets including Auts2 are dosage sensitive and are associated with neurodevelopmental disorders caused by haploinsufficiency.
FMR1 突变是自闭症谱系障碍最常见的可遗传原因。FMR1 编码一种 RNA 结合蛋白，即 FMRP，它与长的、与自闭症相关的转录本结合，对于正常的神经元和卵巢发育至关重要。与普遍认为的 FMRP 作用是阻止翻译延伸的模型相反，我们之前发现 FMRP 激活了果蝇卵母细胞中大量蛋白质的翻译起始。现在，我们提供了证据表明，FMRP 依赖性翻译是保守的，并且发生在哺乳动物大脑中。我们对哺乳动物大脑皮层和果蝇卵母细胞核糖体图谱数据的比较表明，两种物种的 FMRP 缺失组织中，FMRP 结合的 mRNA 的翻译减少到相似的程度。Fmr1 KO 小鼠大脑皮层中几个 FMRP 靶标的稳态水平降低，包括 Auts2 的减少约 50%，Auts2 是一种与常染色体显性自闭症谱系障碍相关的基因。为了区分对延伸和起始的影响，我们使用了一种新的指标来检测限速核糖体停滞。我们没有发现证据表明 FMRP 靶蛋白的产生受翻译延伸率的控制。FMRP 对大蛋白的翻译激活可能对正常的人类发育至关重要，因为包括 Auts2 在内的 20 多个 FMRP 靶标都是剂量敏感的，并且与由单倍不足引起的神经发育障碍有关。
