| NOVEL MECHANISMS OF ESTROGEN ACTION IN
THE DEVELOPING BRAIN: ROLE OF STEROID/NEUROTROPHIN INTERACTIONS
Dominique Toran-Allerand, M.D., Columbia University College of
Physicians & Surgeons, New York, New York
The
organization of neural circuits underlying many sexually-differentiated neuroendocrine,
behavioral and cognitive functions in the adult of both sexes are critically regulated by
early exposure to the gonadal steroid hormones, the estrogens and the androgens. I first
demonstrated that estrogen enhances the growth and differentiation of neurites (both axons
and dendrites) in developing estrogen target forebrain regions, and the extensive
co-localization of estrogen receptors with the mRNAs for the neurotrophin ligands and
their receptor systems (both trk and p75) therein. The neurite-promoting property
of estrogen is expressed only during development and never in the adult female
normally exposed to estrogen. However, in the adult, as a result of the loss of trophic
support, whether through estrogen deprivation, axotomy, or deafferentation, responsiveness
to estrogen returns, and estrogen can again be shown to influence the growth and
differentiation of neurite-derived structures such as axons, dendrites and synapses.
Despite the profound effects of estrogen in early neural development, the molecular
mechanisms underlying these actions are ill-defined. The functional importance of
estrogen/neurotrophin receptor co-expression is supported by our observations of
differential and reciprocal regulation of estrogen and NGF receptor mRNA expression by
their ligands in adult sensory neurons and PC12 cells; and of NGF up-regulation of
estrogen binding sites in PC12 cells and cerebral cortical explants. I will present
evidence suggesting that estrogen and the neurotrophins may influence each other's actions
not only by regulating receptor availability through reciprocal regulation at the level of
gene transcription but also by the sharing of similar, if not overlapping, sequences of
intracellular biochemical events through convergence or cross-coupling of their
signaling pathways. Cross-coupling of converging estrogen and neurotrophin signaling
pathways may result in nuclear end-points that regulate the same broad array of genes
related to neuronal differentiation and neurite growth.
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author(s): |
| D.
Toran-Allerand, M.D., Columbia University College of Physicians & Surgeons, New
York, New York |
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