Mao Hanqian, Pilaz Louis-Jan, McMahon John J, Golzio Christelle, Wu Danwei, Shi Lei, Katsanis Nicholas, Silver Debra L
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710.
Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina 27701, Department of Psychiatry and Behavioral Sciences.
J Neurosci. 2015 May 6;35(18):7003-18. doi: 10.1523/JNEUROSCI.0018-15.2015.
The cerebral cortex is built during embryonic neurogenesis, a period when excitatory neurons are generated from progenitors. Defects in neurogenesis can cause acute neurodevelopmental disorders, such as microcephaly (reduced brain size). Altered dosage of the 1q21.1 locus has been implicated in the etiology of neurodevelopmental phenotypes; however, the role of 1q21.1 genes in neurogenesis has remained elusive. Here, we show that haploinsufficiency for Rbm8a, an exon junction complex (EJC) component within 1q21.1, causes severe microcephaly and defective neurogenesis in the mouse. At the onset of neurogenesis, Rbm8a regulates radial glia proliferation and prevents premature neuronal differentiation. Reduced Rbm8a levels result in subsequent apoptosis of neurons, and to a lesser extent, radial glia. Hence, compared to control, Rbm8a-haploinsufficient brains have fewer progenitors and neurons, resulting in defective cortical lamination. To determine whether reciprocal dosage change of Rbm8a alters embryonic neurogenesis, we overexpressed human RBM8A in two animal models. Using in utero electroporation of mouse neocortices as well as zebrafish models, we find RBM8A overexpression does not significantly perturb progenitor number or head size. Our findings demonstrate that Rbm8a is an essential neurogenesis regulator, and add to a growing literature highlighting roles for EJC components in cortical development and neurodevelopmental pathology. Our results indicate that disruption of RBM8A may contribute to neurodevelopmental phenotypes associated with proximal 1q21.1 microdeletions.
大脑皮层在胚胎神经发生过程中形成，这一时期兴奋性神经元由祖细胞产生。神经发生缺陷可导致急性神经发育障碍，如小头畸形（脑尺寸减小）。1q21.1位点的剂量改变与神经发育表型的病因有关；然而，1q21.1基因在神经发生中的作用仍不清楚。在这里，我们表明，1q21.1内的外显子连接复合体（EJC）成分Rbm8a的单倍剂量不足会导致小鼠出现严重的小头畸形和神经发生缺陷。在神经发生开始时，Rbm8a调节放射状胶质细胞的增殖并防止神经元过早分化。Rbm8a水平降低会导致随后的神经元凋亡，在较小程度上也会导致放射状胶质细胞凋亡。因此，与对照组相比，Rbm8a单倍剂量不足的大脑中祖细胞和神经元较少，导致皮质分层缺陷。为了确定Rbm8a的反向剂量变化是否会改变胚胎神经发生，我们在两种动物模型中过表达了人类RBM8A。使用小鼠新皮质的子宫内电穿孔以及斑马鱼模型，我们发现RBM8A过表达不会显著干扰祖细胞数量或头部大小。我们的研究结果表明，Rbm8a是一种重要的神经发生调节因子，并为越来越多强调EJC成分在皮质发育和神经发育病理学中的作用的文献增添了内容。我们的结果表明，RBM8A的破坏可能导致与近端1q21.1微缺失相关的神经发育表型。
