Dicer-Mediated mTORC1 Signaling and Parathyroid Gland Integrity and Function.
basic_science · Level V
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- Record sourced from PubMed, PMID 38819931.
- Also identified by DOI 10.1681/ASN.0000000000000394 and PMC identifier 11387037.
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Abstract
Maintaining parathyroid gland integrity is a dynamic process regulated by the parathyroid microRNA–mechanistic target of rapamycin complex 1 axis. This axis is essential for preserving intact parathyroid glands throughout life, with relevance to CKD-induced secondary hyperparathyroidism. Secondary hyperparathyroidism of CKD contributes significantly to patient morbidity and mortality. The underlining mechanisms of CKD-induced secondary hyperparathyroidism remain elusive. We previously demonstrated that PT-<i>Dicer</i><sup><i>−/−</i></sup> mice, with parathyroid-specific deletion of the microRNA (miRNA)-processing enzyme <i>Dicer</i> and consequently miRNA, maintain normal basal serum parathyroid hormone (PTH) levels but do not develop secondary hyperparathyroidism induced by CKD. In addition, we showed that the parathyroid mechanistic target of rapamycin complex 1 (mTORC1) pathway is activated in CKD. We now explored the roles of Dicer/miRNA and mTORC1 in parathyroid development and function. We generated mice with parathyroid-specific <i>Dicer</i> (PT-<i>Dicer</i><sup><i>−/−</i></sup>), <i>mechanistic target of rapamycin</i> (PT-<i>mTOR</i><sup><i>−/−</i></sup>), or <i>tuberous sclerosis complex 1</i> (PT-<i>Tsc1</i><sup><i>−/−</i></sup>) deficiency combined with <i>yellow fluorescent protein (YFP)</i> or <i>tdTomato</i> expression to identify the parathyroids by fluorescence microscopy. CKD was induced by an adenine-rich high-phosphate diet. Despite normal basal serum PTH levels, PT-<i>Dicer</i><sup><i>−/−</i></sup> mice displayed apoptotic loss of intact parathyroid glands postnatally and reduced mechanistic target of rapamycin activity. PT-<i>mTOR</i><sup><i>−/−</i></sup> mice lacked intact parathyroid glands yet maintained normal serum PTH levels, mirroring the phenotype of PT-<i>Dicer</i><sup><i>−/−</i></sup> mice. Conversely, PT-<i>Tsc1</i><sup><i>−/−</i></sup> mice with hyperactivated mTORC1 exhibited enlarged glands along with elevated basal serum PTH and calcium levels. Significantly, PT-<i>Dicer</i><sup><i>−/−</i></sup><i>;Tsc1</i><sup><i>−/−</i></sup> double knockout mice preserved intact parathyroid glands and reinstated CKD-induced secondary hyperparathyroidism. mTORC1 operates downstream of Dicer and miRNA in the parathyroid and is essential for maintaining postnatal parathyroid gland integrity throughout life and for the pathogenesis of CKD-induced secondary hyperparathyroidism.