MT1-MMP deficiency leads to defective ependymal cell maturation, impaired ciliogenesis, and hydrocephalus
Zhixin Jiang, … , Guoxiang Jin, Zhongjun Zhou
Zhixin Jiang, … , Guoxiang Jin, Zhongjun Zhou
Published March 31, 2020
Citation Information: JCI Insight. 2020;5(9):e132782. https://doi.org/10.1172/jci.insight.132782.
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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 7

Examination of Notch signaling in lateral ventricles and inhibition of Notch signaling in cultured ECs isolated from mouse brains.

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Examination of Notch signaling in lateral ventricles and inhibition of N...
(A) Representative Western blotting shows the NICD, DLL1, and β-actin expression of LVs from WT and Mmp14–/– brains at P7 and P10. (B) Fold change in mRNA levels of Hes5 and Hey1 in LVs of WT and Mmp14–/– brains at P7 and P10. Gene expression levels in WT samples were designated as 1. Two-tailed Student’s t test, *P < 0.05, **P < 0.01, n = 3. (C) Immunofluorescence staining of γ-tubulin (green) and acetylated α-tubulin (red) in WT and Mmp14–/– ECs cultured in the presence or absence of DAPT for 7 days without serum. Arrows indicate ECs with single cilium. Scale bar: 50 μm. (D and E) Quantification of the percentage of monociliated and multiciliated cells in cultured ECs in the presence or absence of DAPT. (F) Quantification of cilia length in cultured ECs in the presence or absence of DAPT. A total number of 500 cilia per group from 3 independent experiments were measured. One-way ANOVA followed by Tukey’s comparison test, **P < 0.01. Data represent mean ± SEM.