Abnormal development of NG2+PDGFR-α+ neural progenitor cells leads to neonatal hydrocephalus in a ciliopathy mouse model

Abstract

Hydrocephalus is a common neurological disorder leading to expansion of the cerebral ventricles and is associated with significant morbidity and mortality. Most neonatal cases are of unknown etiology and are likely to display complex inheritance involving multiple genes and environmental factors. Identifying molecular mechanisms for neonatal hydrocephalus and developing non-invasive treatment modalities are high priorities. Here we employ 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 PDGFRα signaling, resulting in increased apoptosis and impaired proliferation of NG2+PDGFRα+ neural progenitors. Targeting this pathway with lithium treatment rescued NG2+PDGFRα+ progenitor cell proliferation in BBS mutant mice, reducing ventricular volume. Our findings demonstrate that neural progenitors are critical in the pathogenesis of neonatal hydrocephalus and we identify novel therapeutic targets for this common neurological disorder.

BBS7 is required for BBSome formation and its absence in mice results in Bardet-Biedl syndrome phenotypes and selective abnormalities in membrane protein trafficking

“…Neither do the defective motile cilia appear to be the primary cause of the ventriculomegaly. The abnormal development of neural progenitor cells may underlie the development of ventriculomegaly in this mouse model as demonstrated for other BBS mouse models since both BBS7 and BBS1 are essential for the integrity of the BBSome (Carter et al, 2012). Absence of BBS7 does not affect formation of IFT complexes, although we do not know if the motility of IFT particles is affected by absence of the BBSome.…”

Primary cilia signaling mediates intraocular pressure sensation

“…In the lining of the ventricles, cerebrospinal fluid is also regulated by cilia (18,44). This finding is highlighted by the ciliopathy and hydrocephalus that present in Bardet-Biedl syndrome 1 (BBS1) and BBS3 mutant mice (18,44). Our study shows that cilia in the TM cells of the eye are similarly required for the regulation of pressure, which when dysregulated is strongly implicated in the pathogenesis of glaucoma.…”

“…In the kidney epithelium, ciliary proteins polycystins (PC1/2) are important for flow-dependent calcium flux (43). In the lining of the ventricles, cerebrospinal fluid is also regulated by cilia (18,44). This finding is highlighted by the ciliopathy and hydrocephalus that present in Bardet-Biedl syndrome 1 (BBS1) and BBS3 mutant mice (18,44).…”

An update on research priorities in hydrocephalus: overview of the third National Institutes of Health-sponsored symposium “Opportunities for Hydrocephalus Research: Pathways to Better Outcomes”

“…20,100 In congenital hydrocephalus, reactive astrocytes replace absent ependymal cells at the ventricular border. The role of these astrocytes in the production of proinflammatory and neuroprotective factors is currently under study.…”