Knockdown of Son, a mouse homologue of the ZTTK syndrome gene, causes neuronal migration defects and dendritic spine abnormalities
Knockdown of Son, a mouse homologue of the ZTTK syndrome gene, causes neuronal migration defects and dendritic spine abnormalities
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DOI：
10.1186/s13041-020-00622-4
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发表时间：
2020-05-24
期刊：
影响因子：
3.6
通讯作者：
Nakayama, Atsuo
中科院分区：
文献类型：
--
作者：
Ueda, Masashi;Matsuki, Tohru;Nakayama, Atsuo
Zhu-Tokita-Takenouchi-Kim（ZTTK）综合征是一种罕见的先天性异常综合征，其特征是智力残疾、脑畸形、面部畸形、肌肉骨骼异常和一些内脏畸形，由SON基因的新生杂合突变引起。核蛋白SON参与基因转录和RNA剪接，但SON在神经发育中的作用尚未确定。我们研究了Son敲低对小鼠神经发育的影响，发现神经祖细胞中的Son敲低导致皮质发生期间的迁移缺陷和成熟皮质神经元上的棘密度降低。人类野生型SON表达的诱导挽救了这些神经异常，证实了这些异常是由SON功能不全引起的。我们还将由疾病相关突变体SON基因编码的截短SON蛋白用于拯救实验，并发现由ZTTK综合征中发现的最普遍的SON突变体编码的截短SON蛋白拯救了神经异常，而另一种短得多的突变体SON蛋白没有。这些数据表明，SON功能不全导致神经元迁移缺陷和树突棘异常，这似乎是ZTTK综合征神经症状的神经病理学基础。此外，结果支持ZTTK综合征中的神经异常是由SON单倍不足引起的，与导致功能或功能障碍蛋白的突变类型无关。
Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome, a rare congenital anomaly syndrome characterized by intellectual disability, brain malformation, facial dysmorphism, musculoskeletal abnormalities, and some visceral malformations is caused by de novo heterozygous mutations of the SON gene. The nuclear protein SON is involved in gene transcription and RNA splicing; however, the roles of SON in neural development remain undetermined. We investigated the effects of Son knockdown on neural development in mice and found that Son knockdown in neural progenitors resulted in defective migration during corticogenesis and reduced spine density on mature cortical neurons. The induction of human wild-type SON expression rescued these neural abnormalities, confirming that the abnormalities were caused by SON insufficiency. We also applied truncated SON proteins encoded by disease-associated mutant SON genes for rescue experiments and found that a truncated SON protein encoded by the most prevalent SON mutant found in ZTTK syndrome rescued the neural abnormalities while another much shorter mutant SON protein did not. These data indicate that SON insufficiency causes neuronal migration defects and dendritic spine abnormalities, which seem neuropathological bases of the neural symptoms of ZTTK syndrome. In addition, the results support that the neural abnormalities in ZTTK syndrome are caused by SON haploinsufficiency independent of the types of mutation that results in functional or dysfunctional proteins.