Numb deficiency in cerebellar Purkinje cells impairs synaptic expression of metabotropic glutamate receptor and motor coordination

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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. Significance Protein Numb controls cell fate by interacting with a number of signaling molecules, critical for maintaining neural stem cells and neuronal development in the central nervous system. However, the function of Numb has not been studied in mature neurons. Here, we found that deletion of Numb in cerebellar Purkinje cells causes deficits in motor learning, which can be ascribed to a reduced level of synaptic metabotropic glutamate 1 receptor (mGlu1). Although Numb deficiency does not alter the expression of mGlu1-associated proteins and activity-dependent plasticity of mGlu1, it inhibits intracellular trafficking of mGlu1. To our knowledge, our work is the first to demonstrate an important function of Numb in mature neurons.
Funding Information
  • National Natural Science Foundation of China (31471024)
  • National Natural Science Foundation of China (31271148)
  • National Natural Science Foundation of China (31571051)
  • Natural Science Foundation of Zhejiang Province (Z15C090001)
  • Shenzhen Committee for Technological Renovation (ZDSY20120617112838879)
  • Dutch Organization for Medical Sciences (C.I.D.Z.)
  • Dutch Organization for Life Sciences (C.I.D.Z.)
  • ERC-adv and ERC-POC of the EU (C.I.D.Z.)
  • National Natural Science Foundation of China (31200818)

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