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Abstract: PO0518

The Essential Role of miRNA in Maintaining an Intact Parathyroid in the Adult

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Hassan, Alia, Hadassah Hebrew University Medical Center, Jerusalem, Israel
  • Levin, Rachel, Jerusalem College of Technology, Jerusalem, Jerusalem, Israel
  • Fisher, Yael, Hadassah Hebrew University Medical Center, Jerusalem, Israel
  • Silver, Justin, Hadassah Hebrew University Medical Center, Jerusalem, Israel
  • Ben-Dov, Iddo Z., Hadassah Hebrew University Medical Center, Jerusalem, Israel
  • Naveh-Many, Tally, Hadassah Hebrew University Medical Center, Jerusalem, Israel
Background

miRNA are small noncoding RNAs with vital roles in homeostasis and development. Dicer mediates the final step of miRNA maturation. To study the roles of miRNA in the parathyroid, we generated parathyroid specific Dicer knockout (PT-Dicer-/-) mice, to specifically delete parathyroid miRNA. The PT-Dicer-/- mice had normal serum PTH levels, but failed to increase PTH when stressed by hypocalcemia or kidney failure, unlike control mice and patients. We now show that in addition to parathyroid stimulation, miRNA are central to maintaining intact parathyroid glands throughout life.

Methods

We generated PT-Dicer-/- and control mice expressing YFP (Yellow Fluorescent Protein) in the parathyroid by cre lox recombination, to track parathyroid cells by fluorescence microscopy. Histological slides from P0 (day of birth) and older mice were immunostained. qRT-PCR and Western blots were performed on thyroid tissue that includes the embedded parathyroids.

Results

Surprisingly, adult PT-Dicer-/- mice had no YFP positive parathyroid glands detected by fluorescence microscopy, as opposed to easily detected intact glands in controls. However, the glands were present immediately after birth in P0 and P1 Dicer-/- mice. At P0 and P1 there were increased levels of the cleaved caspase-3 apoptotic marker in cells co-expressing PTH and the parathyroid transcription factor GCM2. From P3 to P12, there was a gradual loss of parathyroid glands in PT-Dicer-/- mice, with the left gland disappearing last. qRT-PCR of thyroid RNA, containing the parathyroid when present, showed reduced expression of PTH mRNA in adult PT-Dicer-/- mice, compared to controls. PTH levels were also decreased in thyroid extracts as determined by Western blots. There was no change in thymus PTH mRNA that has been proposed to provide an auxiliary source of PTH.

Conclusion

Mice that do not express miRNA in the parathyroid lose their parathyroid glands after birth, indicating that miRNA are not essential for parathyroid embryonic development by rather postnatally, for maintaining intact parathyroid glands. In the absence of parathyroid glands in adult PT-Dicer-/- mice, an additional source for PTH other than cells in the thyroid or thymus contributes to normal basal serum PTH that cannot be stimulated by hypocalcemia or uremia.