Ablation of persephin receptor glial cell line-derived neurotrophic factor family receptor alpha4 impairs thyroid calcitonin production in young mice

• Published in: Endocrinology (Philadelphia) 2006-05, Vol.147 (5), p.2237-2244
• Main Authors: Lindfors, Päivi H, Lindahl, Maria, Rossi, Jari, Saarma, Mart, Airaksinen, Matti S
• Format: Article
• Language: English
• Subjects: Animals; Bone and Bones - metabolism; Brain - metabolism; Calcitonin - metabolism; Cell Line; Chromosomes, Artificial, Bacterial - metabolism; Gene Expression Regulation, Developmental; Genetic Vectors; Genotype; Glial Cell Line-Derived Neurotrophic Factor Receptors - biosynthesis; Glial Cell Line-Derived Neurotrophic Factor Receptors - metabolism; Glial Cell Line-Derived Neurotrophic Factor Receptors - physiology; Immunohistochemistry; In Situ Hybridization; Mice; Mice, Knockout; Models, Statistical; Nerve Growth Factors - metabolism; Nerve Tissue Proteins - biosynthesis; Nerve Tissue Proteins - metabolism; Proto-Oncogene Proteins c-ret - metabolism; Receptors, Calcitonin - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Thyroid Gland - cytology; Thyroid Gland - metabolism; Time Factors; Tissue Distribution
• ISSN: 0013-7227

Glial cell line-derived neurotrophic factor family receptor (GFRalpha) 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 GFRalpha4 is produced in mouse only in the C cells but not in parathyroid gland or in the brain. C cells expressed functional GFRalpha4 throughout postnatal development, whereas Ret expression in these cells decreased postnatally and was undetectable in adults. To understand the physiological role of GFRalpha4, we produced GFRalpha4-deficient [knockout (KO)] mice. No differences were observed between wild-type and GFRalpha4-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 GFRalpha4-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 GFRalpha4-KO mice was increased. In conclusion, this study indicates a novel role for endogenous GFRalpha4 signaling in regulating calcitonin production in thyroid C cells of young mice.