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Functional Integrity of ErbB-4/-2 Tyrosine Kinase Receptor Complex in the Hypothalamus Is Required for Maintaining Normal Reproduction in Young Adult Female Rats

Center for Human Molecular Genetics and Department of Cell Biology & 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 & Anatomy, 985455 University of Nebraska Medical Center, Omaha, Nebraska 68198-5455. E-mail: . yma{at}unmc.edu

ErbB-1 tyrosine kinase receptors are necessary for maintaining female reproduction by modulating the release of LH-releasing hormone (LHRH). Changes in ErbB-1 signaling capacity in aging rats are linked to compromised reproduction. The interactive and synergistic nature of different members of ErbB receptors in mediating signal transduction exists in many cellular systems. Particularly, the interactions among ErbB-1 and ErbB-2 or ErbB-4 and ErbB-2 are known to be involved in the stimulation of LHRH secretion during sexual maturation. Thus, ErbB-4/-2 receptors may also play a role in maintaining reproduction during adulthood, and consequently, alteration in ErbB-4/-2 signaling capacity may contribute to compromised reproductive competence during aging. By in situ hybridization histochemistry, ErbB-4/-2 mRNAs were detected in the preoptic area (POA) and arcuate nucleus, which are important areas involved in the control of LHRH neuronal activity. RT-PCR analyses showed that levels of ErbB-4/-2 mRNA increased to a maximal value in the POA of young adult animals before the LH surge. However, no such increase was found in middle-aged female rats. The timing of the decrease in ErbB-4 mRNA in the median eminence-arcuate nucleus of middle-aged rats was delayed compared with that in young adult animals. Disruption of functional ErbB-4/-2 receptor complex by blocking ErbB-2 receptor synthesis in the hypothalamus via an infusion of ErbB-2 antisense oligodeoxynucleotide resulted in an estrous acyclicity in young adult rats. These results indicate that changes in ErbB-4/-2 gene expression and functional integrity of this ErbB-4/-2 receptor complex in the hypothalamus of middle-aged female animals may lead to an altered preovulatory LH release. Thus, the ErbB-4/-2 receptor complex is a physiological component necessary for maintaining female reproduction.

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