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Abstract: TH-PO537

Dicer and MiRNA Deletion Leads to Ectopic Parathyroids

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Hassan, Alia, Hadassah Hebrew University Medical Center, Jerusalem, Jerusalem, Israel
  • Levin, Rachel, Jerusalem College of Technology, Jerusalem, Guinea-Bissau
  • Silver, Justin, Hadassah Hebrew University Medical Center, Jerusalem, Jerusalem, Israel
  • Naveh-Many, Tally, Hadassah Hebrew University Medical Center, Jerusalem, Jerusalem, Israel
Background

Ectopic parathyroid glands are a diagnostic and operative challenge in patients with hyperparathyroidism and are attributed to abnormal embryonic parathyroid migration. miRNA have vital roles in biology and development. The final step of miRNA maturation is mediated by Dicer. We have generated parathyroid specific Dicer knockout (PT-Dicer-/-) mice to specifically delete parathyroid Dicer and miRNAs. The PT-Dicer-/- mice had normal basal serum PTH levels but an impaired increase in PTH in response to acute and chronic hypocalcemia and uremia. Parathyroid glands develop from the parathyroid-thymus common primordia and migrate to their adult location adjacent to the thyroid. We now show that in addition to parathyroid stimulation, Dicer and miRNA are central to parathyroid embryonic development.

Methods

We generated by cre lox recombination mice with parathyroid-specific Dicer knockout (PT-Dicer-/-) and parathyroid specific YFP (PT-YFP), where the parathyroids can be identified under a fluorescence microscope. Mouse thyro/parathyroid histological slides were stained for PTH.

Results

Surprisingly, the parathyroid glands were absent in most thyroid sections of the PT-Dicer-/- mice, despite normal basal PTH. We identified ~75 % of parathyroids in control mice (n=45) but only ~20 % in PT-Dicer-/- and heterozygote PT-Dice+/- mice (n=63 and 14), most of which were small, some showing atypical follicular structures. Heterozygote PT-Dicer+/- mice also had an impaired increase in serum PTH after a low calcium diet, like homozygote PT-Dicer-/- mice, indicating that Dicer haplo-insufficiency abrogates the position of the parathyroid glands and parathyroid stimulation by hypocalcemia. To identify ectopic parathyroids in the PT-Dicer-/- mice, we generated parathyroid specific YFP (PT-YFP) mice. Unlike control PT-YFP mice, 80% of the PT-Dicer-/-; YFP mice had no detectable parathyroid glands. Instead, there were small clusters of ectopic parathyroid cells scattered on the trachea. 20% of the PT-Dicer-/- mice had a single parathyroid gland in the anterior mediastinum or adjacent to the thyroid. These findings explain the absence of parathyroids in thyroid sections of Dicer-/- mice and indicate that Dicer and miRNA are required for parathyroid differentiation and morphogenesis.

Conclusion

Parathyroid Dicer and miRNA are essential for development, migration, localization and function of the parathyroids.

Funding

  • Government Support - Non-U.S.