Abstract
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.
Highlights
Normal brain function requires the precise control of neurogenesis, which is tightly regulated by combinatorial functions of extrinsic signals and intrinsic programs.These authors contributed : Min Wang and Changyong TangElectronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Pathological disturbance of this process contributes to the symptomatology of many neurological disorders
Wdr81f/f adult neural progenitor cells (aNPCs) infected with lentiCreGFP (Wdr81-/- aNPCs) had a significantly lower percentage of BrdU+ cells (Fig. S2c and d) and produced fewer and smaller neurospheres (Fig. S2e–g) than those infected with lenti-dCreGFP (Wdr81+/+ aNPCs)
We investigated the requirement for WDR81 in aNPC differentiation in vitro
Summary
Normal brain function requires the precise control of neurogenesis, which is tightly regulated by combinatorial functions of extrinsic signals and intrinsic programs These authors contributed : Min Wang and Changyong Tang. Pathological disturbance of this process contributes to the symptomatology of many neurological disorders. Endosome-associated signaling receptors can either be delivered to lysosomes for degradation and signal termination, or recycled back to the plasma membrane in a tightly regulated way These events are primarily controlled by endosomal Rab GTPases and phosphoinositides [5,6,7]. It remains largely unknown how PtdIns3P-dependent endosomal trafficking plays a role in adult neurogenesis
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