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Updated: Mar 9, 2026
Evaluation of Planar-Cell-Polarity Phenotypes in Ciliopathy Mouse Mutant Cochlea
Published on: February 21, 2016
Brain ventriculomegaly in Down syndrome mice is caused by Pcp4 dose-dependent cilia dysfunction
Matthieu Raveau1, Takashi Nakahari2, Sachie Asada1
1Laboratory for Neurogenetics, RIKEN, Brain Science Institute, Saitama, Japan.
Abstract:
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.
Insights
Down syndrome causes intellectual disability due to chromosome 21 changes. A specific gene, Pcp4, in Down syndrome mouse models causes brain ventricle enlargement and cilia dysfunction, impacting cerebrospinal fluid flow.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Down syndrome, caused by trisomy 21, is a primary cause of congenital intellectual disability.
- Patients exhibit brain abnormalities impacting cognitive function.
- Previous studies suggested a link between ventriculomegaly and neurogenesis dysfunction in Down syndrome mouse models.
Purpose of the Study:
- To investigate the relationship between trisomic segments and brain phenotypes in Down syndrome.
- To identify the specific genetic cause of ventriculomegaly and cilia dysfunction in a novel Down syndrome mouse model.
- To explore the role of the Pcp4 gene in Down syndrome-related brain abnormalities.
Main Methods:
- Utilized the Ts1Rhr Down syndrome mouse model with a shorter trisomic segment.
- Assessed brain morphology, focusing on ventricular size and ependymal cilia function.
- Investigated the expression of the Pcp4 gene in ependymal cells.
- Performed genetic rescue experiments by normalizing Pcp4 gene copy number.
Main Results:
- The Ts1Rhr model exhibited ventricular enlargement and impaired ependymal cilia beating, independent of neurogenesis defects.
- The Pcp4 gene, located on the trisomic segment, was found to be expressed in ependymal cells.
- Restoring Pcp4 to two copies in Ts1Rhr mice corrected both ventricular enlargement and cilia dysfunction.
Conclusions:
- A trisomic segment, even a short one, can cause specific brain phenotypes in Down syndrome.
- Pcp4 gene dosage is critical for ependymal cell function and cerebrospinal fluid homeostasis.
- This study identifies a Pcp4-dependent ciliopathy contributing to brain dysfunction in Down syndrome.
