Abstract
Hydrocephalus is a common neurological disorder that leads to expansion of the cerebral ventricles and is associated with a high rate of morbidity and mortality. Most neonatal cases are of unknown etiology and are likely to have complex inheritance involving multiple genes and environmental factors. Identifying molecular mechanisms for neonatal hydrocephalus and developing noninvasive treatment modalities are high priorities. Here we use a hydrocephalic mouse model of the human ciliopathy Bardet-Biedl Syndrome (BBS) and identify a role for neural progenitors in the pathogenesis of neonatal hydrocephalus. We found that hydrocephalus in this mouse model is caused by aberrant platelet-derived growth factor receptor α (PDGFR-α) signaling, resulting in increased apoptosis and impaired proliferation of chondroitin sulfate proteoglycan 4 (also known as neuron-glial antigen 2 or NG2)+PDGFR-α+ neural progenitors. Targeting this pathway with lithium treatment rescued NG2+PDGFR-α+ progenitor cell proliferation in BBS mutant mice, reducing their ventricular volume. Our findings demonstrate that neural progenitors are crucial in the pathogenesis of neonatal hydrocephalus, and we identify new therapeutic targets for this common neurological disorder.
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Acknowledgements
We thank L. Biesecker for help obtaining the human MRI scans. We thank K. Rahmouni and D.-F. Guo for help with quantitative RT-PCR and infusion experiments. We thank K. Agassandian for help with dye injection and CSF collection. We thank V. Buffard and L. Qian for their excellent technical assistance. We also appreciate valuable assistance from the University of Iowa Central Microscopy Research Facility. This work was supported in part by US National Institutes of Health grants R01EY110298 and R01EY017168 (to V.C.S.), R01EY022616 (to S.S.), the Knight Templar Eye Foundation (to S.S.) and the Neurosurgery Research and Education Foundation (to T.W.V.). C.S.C. is a National Science Foundation graduate research fellow, and V.C.S. is an Investigator of the Howard Hughes Medical Institute.
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C.S.C., T.W.V. and Q.Z. conceived of the project, designed and performed experiments, coordinated collaborations and wrote the manuscript. S.S. contributed to the experimental design and manuscript revisions. R.E.S. and M.D.C. performed transmission electron microscopy, CSF collection and dye injection experiments and revised the manuscript. T.O.M. coordinated microscopic experiments. K.M.K.-N. and P.N. provided and analyzed human MRI scans. D.R.T. performed MRI for all mice. D.Y.N. and C.C.S. designed and developed the Bbs1 mouse model used in this experiment. K.B. coordinated mouse genotyping and mating. V.C.S. initiated the project, contributed ideas, analyzed and interpreted the results and helped write the manuscript.
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Carter, C., Vogel, T., Zhang, Q. et al. Abnormal development of NG2+PDGFR-α+ neural progenitor cells leads to neonatal hydrocephalus in a ciliopathy mouse model. Nat Med 18, 1797–1804 (2012). https://doi.org/10.1038/nm.2996
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DOI: https://doi.org/10.1038/nm.2996
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