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APPL2 Negatively Regulates Olfactory Functions by Switching Fate Commitments of Neural Stem Cells in Adult Olfactory Bulb via Interaction with Notch1 Signaling

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Abstract

Adult olfactory neurogenesis plays critical roles in maintaining olfactory functions. Newly-generated neurons in the subventricular zone migrate to the olfactory bulb (OB) and determine olfactory discrimination, but the mechanisms underlying the regulation of olfactory neurogenesis remain unclear. Our previous study indicated the potential of APPL2 (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 2) as a modulating factor for neurogenesis in the adult olfactory system. In the present study, we report how APPL2 affects neurogenesis in the OB and thereby mediates olfactory discrimination by using both in vitro neural stem cells (NSCs) and an in vivo animal model—APPL2 transgenic (Tg) mice. In the in vitro study, we found that APPL2 overexpression resulted in NSCs switching from neuronal differentiation to gliogenesis while APPL2 knockdown promoted neurogenesis. In the in vivo study, APPL2 Tg mice had a higher population of glial cells and dampened neuronal production in the olfactory system, including the corpus callosum, OB, and rostral migratory stream. Adult APPL2 Tg mice displayed impaired performance in olfactory discrimination tests compared with wild-type mice. Furthermore, we found that an interaction of APPL2 with Notch1 contributed to the roles of APPL2 in modulating the neurogenic lineage-switching and olfactory behaviors. In conclusion, APPL2 controls olfactory discrimination by switching the fate choice of NSCs via interaction with Notch1 signaling.

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Acknowledgements

This work was supported by Areas of Excellence (AoE/P-705/16) and the General Research Fund, Hong Kong SAR (GRF No. 777313 M). We greatly appreciate the support of the Faculty Core Facility, LKS Faculty of Medicine in The University of Hong Kong for providing technological help with confocal microscopy, dSTORM, and image data analysis.

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  1. Chong Gao and Tingting Yan made equal contributions to the research.

Authors and Affiliations

  1. School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR, China

    Chong Gao, Tingting Yan, Xingmiao Chen & Jiangang Shen

  2. State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR, China

    Kenneth K. Y. Cheng & Aimin Xu

  3. Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR, China

    Kenneth K. Y. Cheng & Aimin Xu

  4. Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China

    Kenneth K. Y. Cheng

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  1. Chong Gao
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Correspondence to Jiangang Shen.

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Gao, C., Yan, T., Chen, X. et al. APPL2 Negatively Regulates Olfactory Functions by Switching Fate Commitments of Neural Stem Cells in Adult Olfactory Bulb via Interaction with Notch1 Signaling. Neurosci. Bull. 36, 997–1008 (2020). https://doi.org/10.1007/s12264-020-00514-6

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