Background: Gonadotropin releasing hormone (GnRH)-secretion is not only regulated by neuronal factors but also by astroglia cells via growth factors (transforming growth factor α (TGFα), neuregulin (NRG)), prostaglandin E2 (PGE2) and the erbB receptor family. Mutations of TGFα and erbB1 result in an impaired reproductive capacity. Mice show a characteristically skin phenotype with wavy hair and curly whiskers. The rat strain SPRD-Cu3 (curly) shows a similar phenotype but the underlying dysfunction has not been elucidated so far.
Objective and hypotheses: This study investigates the significance of the erbB signalling pathway in regulating GnRH neuronal function in curly rats.
Method: Pubertal timing, estrous cyclicity and reproductive performance were analyzed in curly and Sprague Dawley Crl: CD (SD) (control) rats. Primary hypothalamic astrocytic cell cultures were utilized to analyze PGE2 secretion after stimulation of the TGFα-erbB1/erbB2 or NRG-erbB2/erbB4 signalling pathway.
Results: Puberty is delayed in curly compared to control rats (41±0.4 d vs 35±0.3 d, P<0.0001). Their estrous cycle is irregular, experiencing seldom ovulation demonstrated by rare phases of proestrous (10%±1.3 vs 22%±0.8; P<0.0001) and significantly lesser pups per litter compared to controls (6±0.3 vs 11±0.5 pups/litter, P<0.0001). Stimulation of erbB1/erbB2 with TGFα did not show a different release of PGE2 in cell cultures from both rat strains. Moreover, no mutations were present in erbB1 or TGFα. In contrast, stimulation of erbB2/erbB4 signalling pathway with the NRG isoform NRGß2 did not elicit a sufficient PGE2 release in astrocytic cell cultures from curly animals. Whereas, the PGE2 response in controls was significant (P<0.001).
Conclusion: The impaired reproductive capacity and GnRH neuronal function of curly rats is due to a disrupted NRG-erbB2/erbB4 receptor pathway. Further phosphorylation analysis of the erbB4 receptor will proof the functional relevance.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology