The Journal of Neuroscience, April 1, 2003, 23(7):2769
Partial Rescue of the p35
/ Brain Phenotype by Low Expression
of a Neuronal-Specific Enolase p25 Transgene
Holger
Patzke1, 2,
Upendra
Maddineni1, 2,
Ramses
Ayala1,
Maria
Morabito1,
Janet
Volker1,
Pieter
Dikkes3,
Michael K.
Ahlijanian4, and
Li-Huei
Tsai1, 2
1 Department of Pathology and 2 Howard
Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts
02115, 3 Department of Neurology, Children's Hospital,
Boston, Massachusetts 02115, and 4 Department of CNS
Discovery, Pfizer Central Research, Groton, Connecticut 06340
Cyclin-dependent kinase 5 (Cdk5) is activated on binding of
activator proteins p35 and p39. A N-terminally truncated p35, termed
p25, is generated through cleavage by the
Ca2+-dependent protease calpain after induction of
ischemia in rat brain. p25 has been shown to accumulate in brains of
patients with Alzheimer's disease and may contribute to A-
peptide-mediated toxicity. Studies from transfected neurons as well as
p35 and p25 transgenic mice have indicated that Cdk5, when activated by p25, gains some toxic function compared with p35/Cdk5. It remains unclear, however, whether p25/Cdk5 signaling additionally channels into
pathways usually used by p35/Cdk5 and whether p25 is associated with a
loss of p35 function. To clarify these issues, we have generated
p25-transgenic mice in a p35-null background. We find that low levels
of p25 during development induce a partial rescue of the p35
/
phenotype in several brain regions analyzed, including a rescue of cell
positioning of a subset of neurons in the neocortex. In accordance with
the partial rescue of brain anatomy, phosphorylation of the Cdk5
substrate mouse disabled 1 is partially restored during development.
Besides this, p25/Cdk5 fails to phosphorylate other substrates that are
normally phosphorylated by p35/Cdk5. Our results show that p25 can
substitute for p35/Cdk5 under certain circumstances during development.
In addition, they suggest that p25 may have lost some functions of p35.
Key words:
Cdk5; p35; p25; brain; development; phosphorylation; migration; calpain; degeneration
Copyright © 2003 Society for Neuroscience 0270-6474/03/2372769-10$05.00/0
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