Raveau Matthieu, Nakahari Takashi, Asada Sachie, Ishihara Keiichi, Amano Kenji, Shimohata Atsushi, Sago Haruhiko, Yamakawa Kazuhiro
Laboratory for Neurogenetics, RIKEN, Brain Science Institute, Saitama, Japan.
Department of Molecular Cell Physiology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Hum Mol Genet. 2017 Mar 1;26(5):923-931. doi: 10.1093/hmg/ddx007.
Down syndrome is a leading cause of congenital intellectual disability caused by an additional copy of the chromosome 21. Patients display physiological and morphological changes affecting the brain and its function. Previously we showed that Ts1Cje and Ts2Cje, Down syndrome mouse models carrying overlapping trisomic segments of different length, show similar ventriculomegaly and neurogenesis dysfunction leading to the hypothesis of a cause-consequence relationship between these phenotypes. However, we here discovered that Ts1Rhr Down syndrome model, carrying an even shorter trisomic segment, was sufficient to trigger ventricular enlargement and ependymal cilia beating deficiency without affecting neurogenesis. We further found that Pcp4 gene on the Ts1Rhr trisomic segment is expressed in ependymal cells, and its resumption to two copies rescued both ventricular enlargement and cilia dysfunction in Ts1Rhr mice. This work underlines a Pcp4-dependent ciliopathy in Down syndrome brain affecting cerebrospinal fluid flow.
唐氏综合征是由21号染色体额外拷贝导致的先天性智力残疾的主要原因。患者会出现影响大脑及其功能的生理和形态变化。此前我们发现，Ts1Cje和Ts2Cje这两种携带不同长度重叠三体片段的唐氏综合征小鼠模型，表现出相似的脑室扩大和神经发生功能障碍，从而提出了这些表型之间存在因果关系的假设。然而，我们在此发现，携带更短三体片段的Ts1Rhr唐氏综合征模型足以引发脑室扩大和室管膜纤毛跳动缺陷，而不影响神经发生。我们进一步发现，Ts1Rhr三体片段上的Pcp4基因在室管膜细胞中表达，恢复其两个拷贝可挽救Ts1Rhr小鼠的脑室扩大和纤毛功能障碍。这项工作强调了唐氏综合征大脑中一种依赖Pcp4的纤毛病，影响脑脊液流动。
