Aberrant cortical development is driven by impaired cell cycle and translational control in a DDX3X syndrome model.
Aberrant cortical development is driven by impaired cell cycle and translational control in a DDX3X syndrome model.
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DOI：
10.7554/elife.78203
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发表时间：
2022-06-28
期刊：
影响因子：
7.7
通讯作者：
Silver, Debra L.
中科院分区：
文献类型：
--
作者：
Hoye, Mariah L.;Calviello, Lorenzo;Poff, Abigail J.;Ejimogu, Nna-Emeka;Newman, Carly R.;Montgomery, Maya D.;Ou, Jianhong;Floor, Stephen N.;Silver, Debra L.
RNA 解旋酶 DDX3X 的突变是智力障碍的主要原因，并表现为 DDX3X 综合征，这是一种与皮质畸形和自闭症相关的神经发育障碍。然而，DDX3X 控制皮质发育的细胞和分子机制在很大程度上尚不清楚。在这里，使用 Ddx3x 功能丧失的小鼠模型，我们证明 DDX3X 指导神经祖细胞的翻译和细胞周期控制，这是精确皮质生成的基础。首先，我们证明大脑发育对 Ddx3x 剂量敏感；神经祖细胞的 Ddx3x 完全缺失会导致女性小头畸形，而半合子男性和杂合子女性则表现出神经发生减少，但没有明显的小头畸形。此外，Ddx3x 的缺失具有性别二态性，因为它的旁系同源物 Ddx3y 补偿了发育中的男性新皮质中的 Ddx3x。通过祖细胞的实时成像，我们发现 DDX3X 通过调节细胞周期持续时间和神经原性分裂来促进神经元生成。最后，我们使用体内核糖体分析来发现神经祖细胞中翻译转录本的全部内容，包括那些依赖 DDX3X 且对神经发生至关重要的转录本。我们的研究揭示了对 DDX3X 综合征病因学的宝贵新见解，表明祖细胞周期动力学失调和转化是致病机制。在发育过程中，复杂的基因网络确保大脑以正确的方式发育。特别是，它们控制特殊的“祖”细胞在神经发生过程中如何繁殖和成熟以形成神经元。干扰神经发生的基因突变可能导致残疾和缺陷，例如小头畸形，即儿童出生时大脑异常小。 DDX3X 综合征是最近发现的一种疾病，其特征是智力障碍、运动和语言技能延迟获得、肌张力低下，并且经常被诊断为自闭症谱系障碍。当 DDX3X 基因中存在某些突变时，就会出现这种情况，这有助于控制蛋白质在细胞中构建的过程（也称为翻译）。该综合征对女孩的影响比对男孩的影响更大，可能是因为 DDX3X 携带在 X 染色体上。 DDX3X 基因中的许多致病突变也会降低 DDX3X 蛋白的水平。然而，DDX3X 到底控制哪些基因以及它的缺失如何损害大脑发育仍然知之甚少。为了解决这个问题，Hoye 等人。着手研究 Ddx3x 在小鼠神经发生中的作用。对转基因小鼠进行的实验证实，该基因的完全丧失确实会导致出生时大脑尺寸严重缩小。就像患有轻度小头畸形的人类一样，这种情况只存在于受影响的女性中。进一步的遗传学研究揭示了其中的原因：密切相关的 Ddx3y 基因仅存在于 Y（雄性）染色体上，有助于补偿雄性小鼠中 Ddx3x 的缺失。接下来，通过追踪祖细胞的发育方式来检查仅丢失一份 Ddx3x 对神经发生的影响。这可能反映了该综合征患者的 DDX3X 水平。该基因的缺失使细胞分裂更慢，产生的成熟神经细胞更少，这表明 DDX3X 突变引起的大脑尺寸变小和大脑畸形可能是由于神经发生受损所致。最后，一系列进一步的生化和遗传学实验揭示了 DDX3X 蛋白控制下的一组关键基因。这些结果为帮助控制翻译的分子演员如何成为正常大脑发育的关键部分提供了新的线索。这一认识有一天可能有助于改善 DDX3X 综合征和相关神经系统疾病的临床管理或治疗。
Mutations in the RNA helicase, DDX3X, are a leading cause of Intellectual Disability and present as DDX3X syndrome, a neurodevelopmental disorder associated with cortical malformations and autism. Yet, the cellular and molecular mechanisms by which DDX3X controls cortical development are largely unknown. Here, using a mouse model of Ddx3x loss-of-function we demonstrate that DDX3X directs translational and cell cycle control of neural progenitors, which underlies precise corticogenesis. First, we show brain development is sensitive to Ddx3x dosage; complete Ddx3x loss from neural progenitors causes microcephaly in females, whereas hemizygous males and heterozygous females show reduced neurogenesis without marked microcephaly. In addition, Ddx3x loss is sexually dimorphic, as its paralog, Ddx3y, compensates for Ddx3x in the developing male neocortex. Using live imaging of progenitors, we show that DDX3X promotes neuronal generation by regulating both cell cycle duration and neurogenic divisions. Finally, we use ribosome profiling in vivo to discover the repertoire of translated transcripts in neural progenitors, including those which are DDX3X-dependent and essential for neurogenesis. Our study reveals invaluable new insights into the etiology of DDX3X syndrome, implicating dysregulated progenitor cell cycle dynamics and translation as pathogenic mechanisms. During development, a complex network of genes ensures that the brain develops in the right way. In particular, they control how special ‘progenitor’ cells multiply and mature to form neurons during a process known as neurogenesis. Genetic mutations that interfere with neurogenesis can lead to disability and defects such as microcephaly, where children are born with abnormally small brains. DDX3X syndrome is a recently identified condition characterised by intellectual disability, delayed acquisition of movement and language skills, low muscle tone and, frequently, a diagnosis of autism spectrum disorder. It emerges when certain mutations are present in the DDX3X gene, which helps to control the process by which proteins are built in a cell (also known as translation). The syndrome affects girls more often than boys, potentially because DDX3X is carried on the X chromosome. Many of the disease-causing mutations in the DDX3X gene also reduce the levels of DDX3X protein. However, exactly what genes DDX3X controls and how its loss impairs brain development remain poorly understood. To address this problem, Hoye et al. set out to investigate the role of Ddx3x in mice neurogenesis. Experiments with genetically altered mice confirmed that complete loss of the gene indeed caused severe reduction in brain size at birth; just as in humans with mild microcephaly, this was only present in affected females. Further genetic studies revealed the reason for this: the closely related Ddx3y gene, which is only present on the Y (male) chromosome, helped to compensate for the loss of Ddx3x in the male mice. Next, the effect of the loss of just one copy of Ddx3x on neurogenesis was examined by following how progenitor cells developed. This likely reflects DDX3X levels in patients with the syndrome. Loss of the gene made the cells divide more slowly and produce fewer mature nerve cells, suggesting that smaller brain size and brain malformations caused by mutations in DDX3X could be due to impaired neurogenesis. Finally, a set of further biochemical and genetic experiments revealed a key set of genes that are under the control of the DDX3X protein. These results shed new light on how a molecular actor which helps to control translation is a key part of normal brain development. This understanding could one day help improve clinical management or treatments for DDX3X syndrome and related neurological disorders.