Abstract
Aquaporin-4 (AQP4) is expressed in ependymal cells bordering the ventricles, the glia limitans, and pericapillary astrocyte endfeet forming the blood-brain barrier. The sporadic occurrence of obstructive congenital hydrocephalus (OH) has been observed in the offspring of AQP4(-)/(-) mice generated in the CD1 strain background. Here, we used microarray analysis to explore gene expression profiles in the periaqueductal area from littermate AQP4(-)/(-) pups at postnatal day 12. We compared wild-type (WT) animals with AQP4(-)/(-) animals that developed OH (AQP4(-)/(-)-OH) and those that did not (AQP4(-)/(-)-NH). Bioinformatic analysis identified gene sets associated with proliferation and migration of microglia, ependymal cell adhesion, extracellular matrix components, axon myelination, and neuronal synapsis. Among the differentially expressed genes, Spp1-expressed by neonatal CD11c(+) microglia-was highlighted in the triple comparison. Spp1 was significantly upregulated in AQP4(-)/(-)-NH and downregulated in AQP4(-)/(-)-OH mice. These findings suggest that CD11c(+) microglia, via Spp1 expression, play a key morphogenic role in the aqueduct of Sylvius and their absence, occurring in a small subset of AQP4(-)/(-)-CD1 animals, leads to obstructive hydrocephalus.