Spp1 Appears to Be a Key Gene for Sporadic Obstructive Hydrocephalus in the Absence of AQP4

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, <i>Spp1</i>-expressed by neonatal CD11c⁺ microglia-was highlighted in the triple comparison. <i>Spp1</i> was significantly upregulated in AQP4^-/^--NH and downregulated in AQP4^-/^--OH mice. These findings suggest that CD11c⁺ microglia, via <i>Spp1</i> 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.