title: Numb deficiency in cerebellar Purkinje cells impairs synaptic expression of metabotropic glutamate receptor and motor coordination.
abstract: Protein Numb, first identified as a cell-fate determinant in Drosophila, has been shown to promote the development of neurites in mammals and to be cotransported with endocytic receptors in clathrin-coated vesicles in vitro. Nevertheless, its function in mature neurons has not yet been elucidated. Here we show that cerebellar Purkinje cells (PCs) express high levels of Numb during adulthood and that conditional deletion of Numb in PCs is sufficient to impair motor coordination despite maintenance of a normal cerebellar cyto-architecture. Numb proved to be critical for internalization and recycling of metabotropic glutamate 1 receptor (mGlu1) in PCs. A significant decrease of mGlu1 and an inhibition of long-term depression at the parallel fiber-PC synapse were observed in conditional Numb knockout mice. Indeed, the trafficking of mGlu1 induced by agonists was inhibited significantly in these mutants, but the expression of ionotropic glutamate receptor subunits and of mGlu1-associated proteins was not affected by the loss of Numb. Moreover, transient and persistent forms of mGlu1 plasticity were robustly induced in mutant PCs, suggesting that they do not require mGlu1 trafficking. Together, our data demonstrate that Numb is a regulator for constitutive expression and dynamic transport of mGlu1.
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health, Zhejiang University School of Medicine, Hangzhou 310058, China;
authors.forename: Liang
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health, Zhejiang University School of Medicine, Hangzhou 310058, China;
authors.forename: Dong
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health, Zhejiang University School of Medicine, Hangzhou 310058, China;
authors.forename: De-Juan
authors.initials: DJ
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health, Zhejiang University School of Medicine, Hangzhou 310058, China;
authors.forename: Ya-Jun
authors.initials: YJ
authors.lastname: Xie
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health, Zhejiang University School of Medicine, Hangzhou 310058, China;
authors.forename: Jia-Huan
authors.initials: JH
authors.lastname: Zhou
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health, Zhejiang University School of Medicine, Hangzhou 310058, China;
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Institute of Developmental and Regenerative Biology, College of Life and Environmental Science, Hangzhou Normal University, Hangzhou 310029, China;
authors.forename: Hao
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health, Zhejiang University School of Medicine, Hangzhou 310058, China;
authors.forename: Shuo
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health, Zhejiang University School of Medicine, Hangzhou 310058, China;
authors.forename: Chong-Yu
authors.initials: CY
authors.lastname: Shao
authors.affiliation: SARITEX Center for Stem Cell Engineering Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200123, China;
authors.forename: Hua-Shun
authors.initials: HS
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Medicine, University of Virginia, Charlottesville, VA 22908;
authors.forename: J Julius
authors.initials: JJ
authors.lastname: Zhu
authors.affiliation: Institute of Developmental and Regenerative Biology, College of Life and Environmental Science, Hangzhou Normal University, Hangzhou 310029, China;
authors.forename: Meng-Sheng
authors.initials: MS
authors.lastname: Qiu
authors.affiliation: Department of Neuroscience, Erasmus University Medical Center, 3000 CA, Rotterdam, The Netherlands; Netherlands Institute for Neuroscience, Royal Dutch Academy for Arts and Sciences, Meibergdreef 47, Amsterdam, The Netherlands yshen@zju.edu.cn c.dezeeuw@erasmusmc.nl.
authors.forename: Chris I
authors.initials: CI
authors.lastname: De Zeeuw
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health, Zhejiang University School of Medicine, Hangzhou 310058, China; yshen@zju.edu.cn c.dezeeuw@erasmusmc.nl.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shen
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000187:drug effects; D036881:Long-Term Synaptic Depression; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000172:deficiency* / Q000378:metabolism; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D018345:Mice, Knockout; D009024:Morphogenesis / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011689:Purkinje Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C106293:Numb protein, mouse; D018094:Receptors, Metabotropic Glutamate; D008734:Methoxyhydroxyphenylglycol; C010117:3,4-dihydroxyphenylglycol
keywords: Numb; Purkinje cell; cerebellum; mGlu1; trafficking