MT1-MMP deficiency leads to defective ependymal cell maturation, impaired ciliogenesis, and hydrocephalus
Zhixin Jiang, Jin Zhou, Xin Qin, Huiling Zheng, Bo Gao, Xinguang Liu, Guoxiang Jin, Zhongjun Zhou
Zhixin Jiang, Jin Zhou, Xin Qin, Huiling Zheng, Bo Gao, Xinguang Liu, Guoxiang Jin, Zhongjun Zhou
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Research Article Cell biology Development

MT1-MMP deficiency leads to defective ependymal cell maturation, impaired ciliogenesis, and hydrocephalus

Abstract

Hydrocephalus is characterized by abnormal accumulation of cerebrospinal fluid (CSF) in the ventricular cavity. The circulation of CSF in brain ventricles is controlled by the coordinated beating of motile cilia at the surface of ependymal cells (ECs). Here, we show that MT1-MMP is highly expressed in olfactory bulb, rostral migratory stream, and the ventricular system. Mice deficient for membrane-type 1–MMP (MT1-MMP) developed typical phenotypes observed in hydrocephalus, such as dome-shaped skulls, dilated ventricles, corpus callosum agenesis, and astrocyte hypertrophy, during the first 2 weeks of postnatal development. MT1-MMP–deficient mice exhibited reduced and disorganized motile cilia with the impaired maturation of ECs, leading to abnormal CSF flow. Consistent with the defects in motile cilia morphogenesis, the expression of promulticiliogenic genes was significantly decreased, with a concomitant hyperactivation of Notch signaling in the walls of lateral ventricles in Mmp14–/– brains. Inhibition of Notch signaling by γ-secretase inhibitor restored ciliogenesis in Mmp14–/– ECs. Taken together, these data suggest that MT1-MMP is required for ciliogenesis and EC maturation through suppression of Notch signaling during early brain development. Our findings indicate that MT1-MMP is critical for early brain development and loss of MT1-MMP activity gives rise to hydrocephalus.

Authors

Zhixin Jiang, Jin Zhou, Xin Qin, Huiling Zheng, Bo Gao, Xinguang Liu, Guoxiang Jin, Zhongjun Zhou

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Figure 5

Polarity analyses of basal body patches in ependymal cells.

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Polarity analyses of basal body patches in ependymal cells. (A) Represen...
(A) Representative confocal images of whole-mount staining of γ-tubulin (green) and β-catenin (red) in the walls of LVs from WT and Mmp14–/– brains at P10. Scale bar: 20 μm. (B) Distribution of the percentage of cells with different length/width ratios of the basal body patches marked by γ-tubulin staining in A. Contingency table test, P < 0.0001, n = 303 (WT) or n = 339 (KO) cells from 3 mice per genotype. (C) Quantification of average basal body (BB) patch area in the walls of LVs from WT and Mmp14–/– brains at P10. Unpaired Student’s t test, **P < 0.0001. (D) Diagram showing the calculation of basal body displacement. The distance between the centroid of the cell and the centroid of the basal body cluster (d, black line) was normalized to the distance (D, broken line) of the line extended to the cell membrane. (E) Histogram of basal body patch displacement in WT (blue) and Mmp14–/– (red) ependymal cells. Unpaired Student’s t test, **P < 0.0001. (F) Histogram of the distribution of BB patch angles in ependymal cells between WT (blue) and Mmp14–/– (red). Watson’s 2-sample U2 test, **P < 0.01, n = 269 (WT) or n = 300 (KO) cells from 3 mice per genotype.