Integrator complex subunit 15 controls mRNA splicing and is critical for eye development
Integrator complex subunit 15 controls mRNA splicing and is critical for eye development
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整合复合物亚基 15 控制 mRNA 剪接，对眼睛发育至关重要
DOI：
10.1093/hmg/ddad034
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
and Yuki Yamaguchi
中科院分区：
文献类型：
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作者：
Noriyuki Azuma;Tadashi Yokoi;Taku Tanaka;Emiko Matsuzaka;Yuki Saida;Sachiko Nishina;Miho Terao;Shuji Takada;Maki Fukami;Kohji Okamura;Kayoko Maehara;Tokiwa Yamasaki;Jun Hirayama;Hiroshi Nishina;Hiroshi Handa;and Yuki Yamaguchi
眼睛和大脑由精心组织的组织组成，其发育由许多转录因子和发育调节因子的时空精确表达支持。本文报道了整合子复合物亚基15（INTS 15）的分子和遗传学特征，INTS 15是在一个大家系中发现的一个常染色体显性遗传眼病的致病基因。虽然同源的Ints15基因敲除小鼠是胚胎致死的，但缺乏Ints15的小C末端区域的突变小鼠显示出与人类患者相似的眼部畸形。INTS 15在胚胎发育期间在眼和脑中高度表达，并与整合子复合物稳定相互作用以支持小核RNA 3′端加工。它的敲除导致大量基因的错误剪接，可能是次要后果，并严重影响了与眼睛和大脑发育相关的基因。此外，使用人iPS细胞衍生的神经祖细胞的研究表明，INTS 15对视网膜神经节细胞中的轴突生长至关重要。这项研究表明，一般转录机制和高度特异性遗传疾病之间存在新的联系。
The eye and brain are composed of elaborately organized tissues, development of which is supported by spatiotemporally precise expression of a number of transcription factors and developmental regulators. Here we report the molecular and genetic characterization of Integrator complex subunit 15 (INTS15).INTS15was identified in search for the causative gene(s) for an autosomal-dominant eye disease with variable individual manifestation found in a large pedigree. While homozygousInts15knockout mice are embryonic lethal, mutant mice lacking a small C-terminal region of Ints15 show ocular malformations similar to the human patients. INTS15 is highly expressed in the eye and brain during embryogenesis and stably interacts with the Integrator complex to support small nuclear RNA 3′ end processing. Its knockdown resulted in missplicing of a large number of genes, probably as a secondary consequence, and substantially affected genes associated with eye and brain development. Moreover, studies using human iPS cells-derived neural progenitor cells showed that INTS15 is critical for axonal outgrowth in retinal ganglion cells. This study suggests a new link between general transcription machinery and a highly specific hereditary disease.