Research
Neuronal Morphogenesis and Regulation of Nuclear Responses in Mammalian Neurons
We are interested to study the molecular mechanism underlying learning and memory. To achieve this goal, we investigate the functions of protein molecules involved in neuronal morphogenesis, particularly synaptic formation, and the cross talk between synapses and the nuclei of neurons. The functions of CASK protein complex have been focused on.
I. Neuronal Morphogenesis
Syndecan-2, a synaptic transmembrane heparan sulfate proteoglycan, is required for dendritic spinogenesis. Syndecan-2 first induces filopodia formation; filopodia can then transform to mature spines. Via a direct interaction with neurofibromin, a product of Neurofibromatosis type I gene, syndecan-2 activates cAMP pathway and therefore induce the activity of Ena/VASP proteins to promote actin polymerization and filopodia formation. Our preliminary study further suggests that the interaction between syndecan-2 and CASK is involved in the transformation from filopodia to spines or maintenance of dendritic spines.
More neurofibrmoin, CASK, syndecan-2 associated proteins have been identified by yeast two-hybrid screening or proteomic approaches. The studies of these associated proteins in neuronal morphogenesis are in progress.
II. Nuclear function of CASK in neuronal activity
In addition to synapses, CASK also enters the nuclei of neurons, interacts with T-box transcription factor Tbr-1 and nucleosome assembly protein CINAP, and regulates gene expression. The CINAP-CASK-Tbr-1 protein complex controls expression of ion channel NMDAR subunit 2b (NR2b) gene. Moreover, the protein levels of CINAP are regulated by a NMDAR activated proteasomal degradation pathway. Therefore this protein complex may be important for a feedback regulation on homeostasis of neuronal activity. In addition, since NR2b is critical for learning and memory, this protein complex may also play a role in learning behavior. To address this possibility, CASK and CINAP mouse models have been generated. We are in progress to characterize the phenotypes of these mice.
