Mutation in NADPH oxidase 3 (NOX3) impairs SHH signaling and increases cerebellar neural stem/progenitor cell...

Abnormalities in cerebellar structure and function may cause ataxia, a neurological dysfunction of motor coordination. In the course of the present study, we characterized a mutant mouse lineage with an ataxia-like phenotype. We localized the mutation on chromosome 17 and mapped it to position 1534 of the Nox3 gene, resulting in p.Asn64Tyr change. The primary defect observed in Nox3^eqlb mice was increased proliferation of cerebellar granule cell precursors (GCPs). cDNA microarray comparing Nox3^eqlb and BALB/c neonatal cerebellum revealed changes in the expression of genes involved in the control of cell proliferation. Nox3^eqlb GCPs and NSC produce higher amounts of reactive oxygen species (ROS) and upregulate the expression of SHH target genes, such as Gli1-3 and Ccnd1 (CyclinD1). We hypothesize that this new mutation is responsible for an increase in proliferation via stimulation of the SHH pathway. We suggest this mutant mouse lineage as a new model to investigate the role of ROS in neuronal precursor cell proliferation.