Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 50, Pages 15474-15479Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1512915112
Keywords
Numb; mGlu1; trafficking; Purkinje cell; cerebellum
Categories
Funding
- National Natural Science Foundation of China [31471024, 31271148, 31200818, 31571051]
- Natural Science Foundation of Zhejiang Province [Z15C090001]
- Shenzhen Committee for Technological Renovation Grant [ZDSY20120617112838879]
- Dutch Organization for Medical Sciences
- Dutch Life Sciences
- European Research Council (ERC)
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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 cytoarchitecture. 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.
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