Cited2 and PFTAIRE, Two Ways in Which Cyclin Dependent Kinases Impact on Development and Degeneration in the Central Nervous System

Cyclin dependent kinases (Cdks) belong to a large family of evolutionary conserved kinases that are at times divided into mitotic and post-mitotic Cdks, classifications based on their expression/function profile. Neuroblast proliferation rates, differentiation, developmental apoptosis, migration, axogenesis and maintenance are some of the processes which Cdks regulate in the Central Nervous System (CNS). Additionally, Cdks have a role in mature neurons mediating survival/degeneration. Their deregulation has been functionally linked to conditions such as Stroke, Alzheimer's disease and Parkinson's. However, the mechanisms underlying Cdk's involvement in neurons are far from being clear. Accordingly, this thesis research explored two subjects relevant to the functions of Cdks in the CNS: first, the mechanism through which Cited2, a Cdk4-dependent signal, mediates neuronal apoptosis after DNA damage and second, the potential role of PFTAIRE, a post-mitotic Cdk, in CNS development. Cited2, a CBP (cAMP response element-binding protein-binding protein)/p300 interacting transactivator, was identified as a signal upregulated in neurons after DNA damage. We showed that Cdk4 activation is required for Cited2 upregulation and that this event is upstream of mitochondrial cytochrome c release. Additionally, we report that Cited2 activates peroxisome proliferator-activated receptor- (PPAR), an activity that proved to be critical for DNA damage-induced death. We show that these two molecules require each other, forming an active complex that ultimately triggers the mitochondrial pathway of death. Our results not only define a novel Cdk4-mediated neuronal prodeath pathway but report for the first time functional data on Cited2 biological roles in neurons. In the second project, we explored the effects of the deficiency of PFTAIRE, a novel Cdk highly expressed in neurons, in development of the Drosophila ventral nerve cord (VNC). Using two different PFTAIRE Drosophila mutant lines, we demonstrated that the deficiency leads to CNS defects as early as stage 11 of embryonic development. Our findings show that PFTAIRE mutation leads to premature axon outgrowth, axon misguidance and defasciculation accompanied by disorganization of neuronal and glial cell bodies that affect both commissural and longitudinal axons of the VNC. Our data confirms for the first time that PFTAIRE has an essential role in CNS developmental processes and it may be required in neurons for proper axogenesis to occur