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Altered Gene Activity of Epidermal Growth Factor Receptor (ErbB-1) in the Hypothalamus of Aging Female Rat Is Linked to Abnormal Estrous Cycles

Center for Human Molecular Genetics and Department of Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska 68198-5455

Address all correspondence and requests for reprints to: Mark Y. J. Ma, Center for Human Molecular Genetics and Department of Cell Biology and Anatomy, 985455 University of Nebraska Medical Center, Omaha, Nebraska 68198-5455. E-mail: yma{at}unmc.edu

Activation of the ErbB-1 receptor is necessary for initiating mammalian female puberty by stimulating the release of LH-releasing hormone. It remains unclear whether ErbB-1 is also required in governing reproduction during adulthood and whether altered ErbB-1 signaling is linked to changes in gonadotropin secretion in aging females. The present study examined these issues. RT-PCR was employed to determine changes in ErbB-1 mRNA levels during proestrus in both young adult (YA) and middle-aged (MA) female rats. Before the LH surge, expression levels in the preoptic area of YA rats increased to a maximal value. No such increase in ErbB-1 mRNA was found in MA rats. This difference was confirmed by the analysis of in situ hybridization histochemistry, where a stronger mRNA signal was observed in the preoptic area of YA rats compared with MA females. ErbB-1 protein levels measured by Western blot reflected this difference. A peak level of ErbB-1 mRNA in the median eminence-arcuate nucleus was detected at 0800 h in YA rats, but it was delayed in MA animals. There were intense ErbB-1 mRNA-positive cells in the arcuate nucleus. Pharmacological blockade of ErbB-1 receptor-mediated signal transduction resulted in the disruption of estrous cyclicity in YA rats. These results indicate that ErbB-1 receptors are necessary for maintaining normal estrous cycles. Consequently, age-related alterations in hypothalamic ErbB-1 gene activity may contribute to a delayed preovulatory LH secretion in aging females. Thus, the ErbB-1 signaling system plays an important role in the control of female reproduction during adulthood.

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