title: MafB interacts with Gcm2 and regulates parathyroid hormone expression and parathyroid development.
abstract: Serum calcium and phosphate homeostasis is critically regulated by parathyroid hormone (PTH) secreted by the parathyroid glands. Parathyroid glands develop from the bilateral parathyroid-thymus common primordia. In mice, the expression of transcription factor Glial cell missing 2 (Gcm2) begins in the dorsal/anterior part of the primordium on embryonic day 9.5 (E9.5), specifying the parathyroid domain. The parathyroid primordium then separates from the thymus primordium and migrates to its adult location beside the thyroid gland by E15.5. Genetic ablation of gcm2 results in parathyroid agenesis in mice, indicating that Gcm2 is essential for early parathyroid organogenesis. However, the regulation of parathyroid development at later stages is not well understood. Here we show that transcriptional activator v-maf musculoaponeurotic fibrosarcoma oncogene homologue B (MafB) is developmentally expressed in parathyroid cells after E11.5. MafB expression was lost in the parathyroid primordium of gcm2 null mice. The parathyroid glands of mafB(+/-) mice were mislocalized between the thymus and thyroid. In mafB(-/-) mice, the parathyroid did not separate from the thymus. Furthermore, in mafB(-/-) mice, PTH expression and secretion were impaired; expression levels of renal cyp27b1, one of the target genes of PTH, was decreased; and bone mineralization was reduced. We also demonstrate that although Gcm2 alone does not stimulate the PTH gene promoter, it associates with MafB to synergistically activate PTH expression. Taken together, our results suggest that MafB regulates later steps of parathyroid development, that is, separation from the thymus and migration toward the thyroid. MafB also regulates the expression of PTH in cooperation with Gcm2.
authors.affiliation: Laboratory of Molecular and Developmental Biology, Graduate School of Biological Science, Nara Institute of Science and Technology, Ikoma, Japan.
authors.forename: Akiyo
authors.initials: A
authors.lastname: Kamitani-Kawamoto
authors.forename: Michito
authors.initials: M
authors.lastname: Hamada
authors.forename: Takashi
authors.initials: T
authors.lastname: Moriguchi
authors.forename: Masashi
authors.initials: M
authors.lastname: Miyai
authors.forename: Fumie
authors.initials: F
authors.lastname: Saji
authors.forename: Ikuji
authors.initials: I
authors.lastname: Hatamura
authors.forename: Keizo
authors.initials: K
authors.lastname: Nishikawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takayanagi
authors.forename: Seiji
authors.initials: S
authors.lastname: Hitoshi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ikenaka
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Hosoya
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Hotta
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Kataoka
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D007150:Immunohistochemistry; D051258:MafB Transcription Factor / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000378:metabolism*; D010280:Parathyroid Glands / Q000196:embryology*; D010281:Parathyroid Hormone / Q000097:blood / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D017931:DNA Primers; C119532:GCM2 protein, human; D051258:MafB Transcription Factor; C490406:Mafb protein, mouse; D009687:Nuclear Proteins; D010281:Parathyroid Hormone; D014157:Transcription Factors