Deficiency in the Secreted Protein Semaphorin3d Causes Abnormal Parathyroid Development in Mice

J Biol Chem. 2019 May 24;294(21):8336-8347. doi: 10.1074/jbc.RA118.007063. Epub 2019 Apr 12.

Abstract

Primary hyperparathyroidism (PHPT) is a common endocrinopathy characterized by hypercalcemia and elevated levels of parathyroid hormone. The primary cause of PHPT is a benign overgrowth of parathyroid tissue causing excessive secretion of parathyroid hormone. However, the molecular etiology of PHPT is incompletely defined. Here, we demonstrate that semaphorin3d (Sema3d), a secreted glycoprotein, is expressed in the developing parathyroid gland in mice. We also observed that genetic deletion of Sema3d leads to parathyroid hyperplasia, causing PHPT. In vivo and in vitro experiments using histology, immunohistochemistry, biochemical, RT-qPCR, and immunoblotting assays revealed that Sema3d inhibits parathyroid cell proliferation by decreasing the epidermal growth factor receptor (EGFR)/Erb-B2 receptor tyrosine kinase (ERBB) signaling pathway. We further demonstrate that EGFR signaling is elevated in Sema3d -/- parathyroid glands and that pharmacological inhibition of EGFR signaling can partially rescue the parathyroid hyperplasia phenotype. We propose that because Sema3d is a secreted protein, it may be possible to use recombinant Sema3d or derived peptides to inhibit parathyroid cell proliferation causing hyperplasia and hyperparathyroidism. Collectively, these findings identify Sema3d as a negative regulator of parathyroid growth.

Keywords: ERBB signaling; cancer; cell proliferation; development; developmental factor; epidermal growth factor receptor (EGFR); extracellular signaling; hormone; hyperparathyroidism; parathyroid hormone; parathyroid hyperplasia; proliferation; receptor tyrosine kinase; semaphorin signaling; signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Hyperparathyroidism, Primary / epidemiology*
  • Hyperparathyroidism, Primary / genetics
  • Hyperparathyroidism, Primary / pathology
  • Mice
  • Mice, Knockout
  • Parathyroid Glands / embryology*
  • Parathyroid Glands / pathology
  • Semaphorins / deficiency*
  • Semaphorins / metabolism
  • Signal Transduction*

Substances

  • Sema 3D protein, mouse
  • Semaphorins
  • EGFR protein, mouse
  • ErbB Receptors