Prader-Willi syndrome protein necdin regulates the nucleocytoplasmic distribution and dopaminergic neuron development

Dopamine (DA) plays important roles in various behaviors, including learning and motivation. Recently, THOC5 was identified as an important regulator in the development of dopaminergic neurons. However, how THOC5 is regulated has not been explored. In this study, we found an interaction between THOC5 and necdin, which is encoded by a gene located in the chromosome deletion region of Prader-Willi syndrome (PWS), by using a yeast two-hybrid assay. Necdin affects the mRNA export function of THOC5 by regulating its nucleocytoplasmic localization. As a result, the expression of a few DA neuronal development-related genes, such as Mef2c, Lef1 and Prkcg, is altered in necdin-deficient mice. We also found neurodegeneration of dopaminergic neurons and an increase of glial cells in necdin-deficient mice, which may underlie the dyspraxia behaviors in these mice. Our results thus identified necdin as a novel regulator for THOC5, which may underlie, at least partly, the abnormal DA neuron development in necdin-deficient mice.