Minor spliceosome inactivation causes microcephaly, owing to cell cycle defects and death of self-amplifying radial glial cells
Minor spliceosome inactivation causes microcephaly, owing to cell cycle defects and death of self-amplifying radial glial cells
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DOI：
10.1242/dev.166322
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发表时间：
2018-09-01
期刊：
影响因子：
4.6
通讯作者：
Kanadia, Rahul N.
中科院分区：
文献类型：
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作者：
Baumgartner, Ma Beth;Olthof, Anouk M.;Kanadia, Rahul N.
小剪接体成分的突变与发育障碍性小头骨发育不良性原始侏儒症1型（MOPD 1）有关。在这里，我们通过消融Rnu 11来灭活发育中的小鼠皮层（paleostomy）中的次要剪接体，Rnu 11编码关键的次要剪接体小核RNA（snRNA）U11。Rnu 11条件性基因敲除小鼠出生时患有小头畸形，这是由自扩增放射状胶质细胞（RGCs）死亡引起的，而中间祖细胞和神经元则产生了。RNA测序表明，这种细胞死亡是由p53（Trp 53-小鼠基因组信息学）和DNA损伤的上调介导的，这两者都是在U11缺失的RGC中特异性观察到的。此外，U11的损失导致升高的小内含子保留在基因调节细胞周期，这是一致的RGCs在S期和胞质分裂，以及延长中期的RGCs。总之，我们发现自扩增RGC是对次要剪接损失最敏感的细胞类型。总之，这些发现提供了一个潜在的解释，如何破坏小剪接可能会导致小头畸形MOPD 1。
Mutation in minor spliceosome components is linked to the developmental disorder microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1). Here, we inactivated the minor spliceosome in the developing mouse cortex (pallium) by ablating Rnu11, which encodes the crucial minor spliceosome small nuclear RNA (snRNA) U11. Rnu11 conditional knockout mice were born with microcephaly, which was caused by the death of self-amplifying radial glial cells (RGCs), while intermediate progenitor cells and neurons were produced. RNA sequencing suggested that this cell death was mediated by upregulation of p53 (Trp53 - Mouse Genome Informatics) and DNA damage, which were both observed specifically in U11-null RGCs. Moreover, U11 loss caused elevated minor intron retention in genes regulating the cell cycle, which was consistent with fewer RGCs in S-phase and cytokinesis, alongside prolonged metaphase in RGCs. In all, we found that self-amplifying RGCs are the cell type most sensitive to loss of minor splicing. Together, these findings provide a potential explanation of how disruption of minor splicing might cause microcephaly in MOPD1.