ErbB4 point mutation in CU3 inbred rats affects gonadotropin-releasing-hormone neuronal function via compromised neuregulin-stimulated prostaglandin E2 release from astrocytes

Gonadotropin releasing hormone (GnRH)-secretion is not only regulated by neuronal factors but also by astroglia cells via growth factors and ErbB receptors of the epidermal growth factor family. Studies in transgenic mice carrying mutations in the ErbB receptor system experience impaired reproductive capacity. In addition, some of these animals show a typical skin phenotype with wavy hair and curly whiskers. The rat strain SPRD-CU3 (CU3), examined in this study, displays a similar skin phenotype and a significant impairment of the timing of puberty onset and reproductive performance, suggesting a disruption in the astrocytic to GnRH neuronal communication. To address this issue, we analyzed astrocytic prostaglandin E₂ (PGE₂) release from primary hypothalamic astrocytic cell cultures after stimulation with transforming growth factor α (TGFα), ligand for ErbB1/ErbB2, or Neuregulin 1 beta 2 (NRG1ß₂), ligand for ErbB4/ErbB2 signaling pathway. Compared to cultures from wild type animals, astrocytic cultures from CU3 rats were unable to respond to NRG stimulation, suggesting a disruption of the ErbB4/ErbB2 signaling pathway. This is confirmed by mutational analysis of ErbB4 that revealed a single point mutation at 3125 bp resulting in an amino acid change from proline to glutamine located at the carboxy-terminal region. As a consequence, substantial conformational changes occur in the transmembrane and intracellular domain of the protein, affecting the ability to form a receptor dimer with a partner and the ability to function as a transcriptional regulator. Thus, astroglia to GnRH neuronal signaling via ErbB4 is essential of timely onset of puberty and reproductive function.