Ablation of persephin receptor glial cell line-derived neurotrophic factor family receptor α4 impairs thyroid calcitonin production in young mice

Glial cell line-derived neurotrophic factor family receptor (GFR alpha) 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 GFR alpha 4 is produced in mouse only in the C cells but not in parathyroid gland or in the brain. C cells expressed functional GFR alpha 4 throughout postnatal development, whereas Ret expression in these cells decreased postnatally and was undetectable in adults. To understand the physiological role of GFR alpha 4, we produced GFR alpha 4-deficient [knockout (KO)] mice. No differences were observed between wild-type and GFR alpha 4-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 GFR alpha 4-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 GFR alpha 4-KO mice was increased. In conclusion, this study indicates a novel role for endogenous GFR alpha 4 signaling in regulating calcitonin production in thyroid C cells of young mice.