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Ablation of Persephin Receptor Glial Cell Line-Derived Neurotrophic Factor Family Receptor 4 Impairs Thyroid Calcitonin Production in Young Mice

Neuroscience Center (P.H.L., J.R., M.S.A.), and Institute of Biotechnology (M.L., M.S.), University of Helsinki, FIN-00014 Helsinki, Finland

Address all correspondence and requests for reprints to: Matti S. Airaksinen, Neuroscience Center, Viikinkaari 4 (P.O. Box 56), University of Helsinki, FIN-00014 Helsinki, Finland. E-mail: mairaksi{at}operoni.helsinki.fi.

Glial cell line-derived neurotrophic factor family receptor (GFR) 4, the binding receptor for persephin, is coexpressed with the signaling Ret receptor tyrosine kinase predominantly in thyroid calcitonin-producing C cells. We show by in situ hybridization and immunohistochemistry that the functional, glycolipid-anchored form of GFR4 is produced in mouse only in the C cells but not in parathyroid gland or in the brain. C cells expressed functional GFR4 throughout postnatal development, whereas Ret expression in these cells decreased postnatally and was undetectable in adults. To understand the physiological role of GFR4, we produced GFR4-deficient [knockout (KO)] mice. No differences were observed between wild-type and GFR4-KO littermate animals in growth, gross behavior, or viability. The number and morphology of the thyroid C cells were indistinguishable between the genotypes in both newborn and adult age. However, thyroid tissue calcitonin content was reduced by 60% in newborn and by 45% in 3-wk-old GFR4-KO mice compared with wild-type controls. In contrast, thyroid calcitonin levels were similar in adult animals. Consistent with the reduced calcitonin levels, bone formation rate in juvenile GFR4-KO mice was increased. In conclusion, this study indicates a novel role for endogenous GFR4 signaling in regulating calcitonin production in thyroid C cells of young mice.

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