The midregion, nuclear localization sequence, and C terminus of PTHrP regulate skeletal development, hematopoiesis, and survival in mice

Ramiro E. Toribio, Holly A. Brown, Chad M. Novince, Brandlyn Marlow, Krista Hernon, Lisa G. Lanigan, Blake E. Hildreth, Jillian L. Werbeck, Sherry T. Shu, Gwendolen Lorch, Michelle Carlton, John Foley, Prosper Boyaka, Laurie K. McCauley, Thomas J. Rosol

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

The functions of parathyroid hormonerelated protein (PTHrP) on morphogenesis, cell proliferation, apoptosis, and calcium homeostasis have been attributed to its N terminus. Evidence suggests that many of these effects are not mediated by the N terminus but by the midregion, a nuclear localization sequence (NLS), and C terminus of the protein. A knock-in mouse lacking the midregion, NLS, and C terminus of PTHrP (PthrpΔ/Δ) was developed. PthrpΔ/Δ mice had craniofacial dysplasia, chondrodysplasia, and kyphosis, with most mice dying by d 5 of age. In bone, there were fewer chondrocytes and osteoblasts per area, bone mass was decreased, and the marrow was less cellular, with erythroid hypoplasia. Cellular proliferation was impaired, and apoptosis was increased. Runx2, Ocn, Sox9, Crtl1, β-catenin, Runx1, ephrin B2, cyclin D1, and Gata1 were underexpressed while P16/Ink4a, P21, GSK-3β, Il-6, Ffg3, and Ihh were overexpressed. Mammary gland development was aberrant, and energy metabolism was deregulated. These results establish that the midregion, NLS, and C terminus of PTHrP are crucial for the commitment of osteogenic and hematopoietic precursors to their lineages, and for survival, and many of the effects of PTHrP on development are not mediated by its N terminus. The down-regulation of Runx1, Runx2, and Sox9 indicates that PTHrP is a modulator of transcriptional activation during stem cell commitment.

Original languageEnglish (US)
Pages (from-to)1947-1957
Number of pages11
JournalFASEB Journal
Volume24
Issue number6
DOIs
StatePublished - Jun 1 2010

Keywords

  • Craniofacial
  • Lethality
  • Osteoblast
  • Parathyroid

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

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    Toribio, R. E., Brown, H. A., Novince, C. M., Marlow, B., Hernon, K., Lanigan, L. G., Hildreth, B. E., Werbeck, J. L., Shu, S. T., Lorch, G., Carlton, M., Foley, J., Boyaka, P., McCauley, L. K., & Rosol, T. J. (2010). The midregion, nuclear localization sequence, and C terminus of PTHrP regulate skeletal development, hematopoiesis, and survival in mice. FASEB Journal, 24(6), 1947-1957. https://doi.org/10.1096/fj.09-147033