The Journal of Neuroscience, August 15, 1999, 19(16):6994-7006
Overlapping and Divergent Actions of Estrogen and the
Neurotrophins on Cell Fate and p53-Dependent Signal Transduction in
Conditionally Immortalized Cerebral Cortical Neuroblasts
Stephen B.
Wade,
Prem
Oommen,
William C.
Conner,
David J.
Earnest, and
Rajesh C.
Miranda
Texas A & M University Health Science Center, Department of Human
Anatomy and Medical Neurobiology, College Station, Texas 77843-1114
The developing cerebral cortex undergoes overlapping periods of
neurogenesis, suicide, and differentiation to generate the mature
cortical plate. The following experiments examined the role of the
gonadal hormone estrogen in comparison to the neurotrophins, in the
regulation of p53-dependent cortical cell fate. To synchronize choices
between neurogenesis, apoptosis, and neural differentiation, embryonic
rat cerebral cortical neuroblasts were conditionally immortalized with
the SV40 large T antigen containing the tsA58/U19 temperature-sensitive mutations. At the nonpermissive temperature, cessation of large T antigen expression was accompanied by induction of
p53, as well as the p53-dependent proteins, wild-type p53-activated fragment-1/Cdk (cyclin-dependent kinase)-interacting protein-1 (p21/Waf1), Bcl (B-cell lymphoma)-associated protein
(Bax), and murine double minute 2 (MDM2), that lead to cell
cycle-arrest, suicide, and p53 inhibition, respectively.
Simultaneously, neuroblasts exit cell cycle and die apoptotically or
differentiate primarily into astrocytes and immature postmitotic
neuroblasts. At the nonpermissive temperature, estrogen specifically
induced an antagonist-independent increase in phosphorylated p53
expression, while increasing p21/Waf1 and decreasing Bax.
Coincidentally, estrogen rapidly increased and then decreased MDM2
relative to controls, suggesting temporal modulation of p53 function.
Both estrogen and neurotrophins prevented DNA fragmentation, a marker
for apoptosis. However, estrogen also induced a transient increase in
released lactate dehydrogenase, suggesting that estrogen simultaneously
induced rapid cell death in a subpopulation of cells. In contrast to
the neurotrophins, estrogen also increased cell proliferation. Both
estrogen and the neurotrophins supported neuronal differentiation.
However, in contrast to the neurotrophins, estrogen only supported the expression of a subset of oligodendrocytic markers. These results suggest that estrogen and the neurotrophins support overlapping and
distinct aspects of differentiation in the developing cerebral cortex.
Key words:
estradiol-17
; tamoxifen; nerve growth factor; brain
derived neurotrophic factor; neurotrophin-3; neurotrophin-4; large T
antigen; apoptosis; necrosis; cell cycle, bromodeoxyuridine; nestin; neurofilament; glial fibrillary acidic protein; galactocerebroside; 2',3'-cyclic nucleotide-3'-phosphodiestrase; neurons; astrocytes; oligodendrocytes; stem cells; p53; MDM2; p21/Waf1; Bax
Copyright © 1999 Society for Neuroscience 0270-6474/99/19166994-13$05.00/0
Previous Article | Next Article
