Ablation of persephin receptor glial cell line-derived neurotrophic factor family receptor alpha4 impairs thyroid calcitonin production in young mice.
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.
Neuroscience Center, University of Helsinki, Finland.
Päivi H
PH
Lindfors
Maria
M
Lindahl
Jari
J
Rossi
Mart
M
Saarma
Matti S
MS
Airaksinen
D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002116:Calcitonin / Q000378:metabolism; D002460:Cell Line; D022202:Chromosomes, Artificial, Bacterial / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005822:Genetic Vectors; D005838:Genotype; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D015233:Models, Statistical; D009414:Nerve Growth Factors / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018003:Receptors, Calcitonin / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013961:Thyroid Gland / Q000166:cytology / Q000378:metabolism*; D013997:Time Factors; D014018:Tissue Distribution
C412547:Gfra4 protein, mouse; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D018003:Receptors, Calcitonin; C110758:persephin; C510373:persephin receptor, mouse; D002116:Calcitonin; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse