Cdk5 promotes synaptogenesis by regulating the subcellular distribution of the MAGUK family member CASK.
Synaptogenesis is a highly regulated process that underlies formation of neural circuitry. Considerable work has demonstrated the capability of some adhesion molecules, such as SynCAM and Neurexins/Neuroligins, to induce synapse formation in vitro. Furthermore, Cdk5 gain of function results in an increased number of synapses in vivo. To gain a better understanding of how Cdk5 might promote synaptogenesis, we investigated potential crosstalk between Cdk5 and the cascade of events mediated by synapse-inducing proteins. One protein recruited to developing terminals by SynCAM and Neurexins/Neuroligins is the MAGUK family member CASK. We found that Cdk5 phosphorylates and regulates CASK distribution to membranes. In the absence of Cdk5-dependent phosphorylation, CASK is not recruited to developing synapses and thus fails to interact with essential presynaptic components. Functional consequences include alterations in calcium influx. Mechanistically, Cdk5 regulates the interaction between CASK and liprin-alpha. These results provide a molecular explanation of how Cdk5 can promote synaptogenesis.
Howard Hughes Medical Institute, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Benjamin Adam
BA
Samuels
Yi-Ping
YP
Hsueh
Tianzhi
T
Shu
Haoya
H
Liang
Huang-Chun
HC
Tseng
Chen-Jei
CJ
Hong
Susan C
SC
Su
Janet
J
Volker
Rachael L
RL
Neve
David T
DT
Yue
Li-Huei
LH
Tsai
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics; D015220:Calcium Channels / Q000502:physiology; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D051360:Cyclin-Dependent Kinase 5 / Q000502:physiology*; D051528:Guanylate Kinases / Q000378:metabolism*; D007136:Immunoglobulins / Q000096:biosynthesis / Q000235:genetics; D015640:Ion Channel Gating / Q000502:physiology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D010766:Phosphorylation; D017729:Presynaptic Terminals / Q000502:physiology; D011506:Proteins / Q000235:genetics; D020239:Receptor Cross-Talk / Q000502:physiology; D013347:Subcellular Fractions / Q000378:metabolism*; D013569:Synapses / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; C498598:Cadm1 protein, mouse; D015220:Calcium Channels; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D008565:Membrane Proteins; C477798:Ppfia1 protein, mouse; D011506:Proteins; C106868:CASK kinases; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D051528:Guanylate Kinases