WDR81 regulates adult hippocampal neurogenesis through endosomal SARA-TGFβ signaling

Adult hippocampal neurogenesis, a process considered important for hippocampal function, is regulated at multiple molecular levels. Mutations in the gene encoding the WD40 repeat-containing protein WDR81 are associated with neurological disorders, including cerebellar ataxia, mental retardation, quadrupedal locomotion syndrome (CAMRQ2), and microcephaly. In this study, we show that ablation of WDR81 in adult neural progenitor cells (aNPCs) markedly reduced adult hippocampal neurogenesis and impaired hippocampus-dependent learning. WDR81 suppresses endosomal PtdIns3P synthesis, likely by inhibiting the assembly of the PI3K-III complex. In the absence of WDR81, endosomal PtdIns3P levels are greatly elevated, leading to endosomal persistence of the PtdIns3P-binding protein SARA and consequently hyperactivation of SARA-dependent TGFβ signaling. Inhibition of PI3K-III activity or suppression of SARA-dependent TGFβ signaling markedly ameliorated the defective adult neurogenesis in WDR81-deficient mice. Taken together, these findings not only uncover the requirement for the WDR81–SARA–TGFβ axis in adult hippocampal neurogenesis, but also suggest that defective adult hippocampal neurogenesis contributes to the etiology of WDR81-related neurological diseases.