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

TL;DR

This study finds that the gene Spp1, expressed by microglia, plays a key role in preventing hydrocephalus in mice lacking AQP4.

Contribution

The study identifies Spp1 as a novel key gene involved in sporadic obstructive hydrocephalus in AQP4-deficient mice.

Findings

Spp1 is significantly upregulated in AQP4−/−-NH mice and downregulated in AQP4−/−-OH mice.

CD11c+ microglia expressing Spp1 appear to have a morphogenic role in the aqueduct of Sylvius.

The absence of Spp1 in a subset of AQP4−/−-CD1 mice leads to obstructive hydrocephalus.

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.

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