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The Journal of Neuroscience, March 1, 2001, 21(5):1481-1489
Insulin-Like Growth Factor-I Overexpression Attenuates Cerebellar Apoptosis by Altering the Expression of Bcl Family Proteins in a Developmentally Specific Manner
Dionisios Chrysis, Ali Suha Calikoglu, Ping Ye, and A. Joseph D'Ercole Department of Pediatrics, The University of North Carolina, Chapel Hill, North Carolina 27599-7220
In studies of transgenic (Tg) mice that overexpress insulin-like growth factor-I (IGF-I) exclusively in the CNS, we demonstrated a dramatic increase in cerebellar granule cell number that appeared to be attributable predominantly to enhanced survival. IGF-I anti-apoptotic actions are well established in cultured neurons, but comparable studies in vivo are few. Using the same Tg mice, therefore, we set out to document IGF-I anti-apoptotic effects during cerebellar development and to probe IGF-I signaling mechanisms. Compared with cerebella (CBs) of non-Tg littermates, those of Tg mice had fewer apoptotic cells at postnatal day 7 (P7) and showed a similar tendency at P14 and P21. At each age studied, procaspase-3 and caspase-3 were decreased in CBs of Tg mice. The caspase-3 decline was accompanied by decreases in the 85 kDa fragment of Poly(ADP-ribose) polymerase, a known product of caspase cleavage, suggesting decreased caspase activity. At P7 decreased apoptosis in Tg mice was associated with increased expression of the anti-apoptotic Bcl genes, Bcl-xL and Bcl-2. The mRNA expression of the proapoptotic Bcl genes, Bax and Bad, also was increased, but no changes were observed in the abundance of their proteins. At P14 Bcl-xL and Bcl-2 expression were similar in normal and Tg mice; Bax mRNA was unchanged in Tg mice, but its protein abundance was decreased, and both Bad mRNA and protein abundance were decreased. At P21 Bcl-xL and Bcl-2 expression were unchanged, but Bax and Bad expression were decreased. Our data show that IGF-I exerts anti-apoptotic actions during cerebellar development, and thereby alters the magnitude of naturally occurring apoptosis. IGF-I appears to affect multiple steps in the apoptotic pathway in a developmentally specific manner. IGF-I decreases caspase-3 availability and activity, increases the expression of anti-apoptotic Bcl-xL and Bcl-2 during early postnatal development, and decreases proapoptotic Bax and Bad expression at later developmental stages.
Key words: IGF-I; apoptosis; cerebellum; development; transgenic mice; Bcl; Bcl-2; Bcl-xL; Bad; Bax; caspase-3; Poly(ADP-ribose) polymerase
Copyright © 2001 Society for Neuroscience 0270-6474/01/2151481-09$05.00/0
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