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Department of Cell Biology (E.M.A., J.E.L., J.H.C., B.W.O.)
Baylor College of Medicine Houston, Texas 77030-3498
Department of Pathophysiology (J.G.) University Medical
School of Pécs Pécs, Hungary
Sex steroids exert profound influence on neural
development and function through activation of intranuclear receptors.
However, during sexual differentiation and at onset of puberty,
intracerebral estrogen (E) availability is subsequent to these effects.
The potent mitogen epidermal growth factor (EGF) activates estrogen
receptor (ER)-dependent transcription in cultured cells in the absence
of exogenous E. Since reproductive behavior in female rodents is the
result of E-dependent transcriptional activity and protein synthesis,
lordosis serves as a well established in vivo model for
probing cellular and molecular mechanisms of steroid receptor-dependent
behavior. Here we demonstrate that EGF can signal through the classical
E receptor (ER
) to alter in vivo function in rodent
central nervous system. EGF and EGF receptor ligands induced
lordosis in a dose- and time-dependent manner in the absence of steroid
treatment in ovariectomized rats and mice. Using antisense
oligonucleotides, pharmacological and antibody blockade, and mutant
mice, we also report that this behavioral responsiveness is mediated
through ER by specific stimulation of membrane-bound EGF receptors
and EGF receptor-specific tyrosine kinase rather than by direct ligand
activation of the ER. Of biological significance, delayed onset of
puberty and the absence of synchronization between reproductive
behavior and ovulation was detected in intact mutant Wa-2 mice that
express a naturally occurring point mutation in the EGF receptor. To
our surprise, EGF-mediated behavior was independent of progesterone (P)
and progesterone receptor (PR) since antiprogestins, PR antisense
oligonucleotides, and targeted disruption of PR in ovariectomized
transgenic mice failed to impede the display of lordosis after EGF.
Finally, we also found that another growth factor, insulin-like growth
factor-1, which provokes ER-dependent transcription in
vitro, activates mating behavior in a similar E-independent
manner. Thus, growth factor mediation of ER-targeted function may be a
universal feature in the rodent central nervous system, raising
critical questions about the role of growth factors in mediating
ER-dependent processes in development and reproduction.
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