WDR81 regulates adult hippocampal neurogenesis through endosomal SARA-TGFβ signaling

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.

Reduction of WDR81 impairs autophagic clearance of aggregated proteins and cell viability in neurodegenerative phenotypes

“…Recently, Guo's group reported that loss of WDR81 in adult neural progenitor cells significantly reduced adult neurogenesis in hippocampus and impaired hippocampus-dependent learning [35]. Thus, this study supports our conclusion that WDR81 reduction is the one of the causes of neurodegenerative disorders.…”

Developmental Cytoplasmic-to-Nuclear Translocation of RNA-Binding Protein HuR Is Required for Adult Neurogenesis

“…Immunocytochemistry staining was carried out as described (Wang et al, 2018). Briefly, aNPCs were preblocked using PBS containing 5% normal goat serum (VECTOR, #S-1000) and 0.1% Triton X-100 for 30 min, followed by overnight incubation with primary antibodies.…”

“…Neural Stem Cells (NSCs) In Vitro Assay Proliferation and differentiation analyses were performed as described previously (Wang et al, 2018). To study cell proliferation, we dissociated aNSCs with trypsin and plated them on poly-L-ornithin/laminin-coated slides (Nunc, #154526) at a density of 50,000 cells/well in proliferation medium.…”

“…HuR conditional knockout mouse line (HuR-cKO) were generated by crossing HuR flox/flox mouse (Ghosh et al, 2009) with EMX1-Cre driver mouse (Gorski et al, 2002). HuR inducible conditional knockout mouse line (HuR-iKO) were generated by crossing HuR flox/flox mouse (Ghosh et al, 2009) with Nestin-CreERT2 mouse (Tang et al, 2019) and Rosa26-loxp-stop-loxp-CAG-DTR-2A-EGFP mouse (Wang et al, 2018) or Rosa26-loxp-stop-loxp-Tdtomato reporter mouse (Vitalstar). In experiments involving HuR-cKO mice, we used time pregnant female mice.…”

Endosomal trafficking defects alter neural progenitor proliferation and cause microcephaly

“…Our data point to the intracellular processing of EGFR as an important level of control for the regulation of proliferation in radial glial cells. WDR81 is likely to affect the trafficking of other cargos 40 , which may also impact cell radial glial cell proliferation. Moreover, the trafficking of neuronal cargoes, such as adhesion molecules, is likely to lead to the altered neuronal positioning observed in KO mice, and to the lissencephaly phenotype in human.…”