SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts.

TitleSLITRK5 is a negative regulator of hedgehog signaling in osteoblasts.
Publication TypeJournal Article
Year of Publication2021
AuthorsSun J, Shin DYeon, Eiseman M, Yallowitz AR, Li N, Lalani S, Li Z, Cung M, Bok S, Debnath S, Marquez SJenia, White TE, Khan AG, Lorenz IC, Shim J-H, Lee FS, Xu R, Greenblatt MB
JournalNat Commun
Date Published2021 07 29
KeywordsAnimals, Cell Differentiation, Cells, Cultured, Cilia, Hedgehog Proteins, Humans, Membrane Proteins, Mice, Mice, Knockout, Nerve Tissue Proteins, Osteoblasts, Osteogenesis, Patched-1 Receptor, Signal Transduction

Hedgehog signaling is essential for bone formation, including functioning as a means for the growth plate to drive skeletal mineralization. However, the mechanisms regulating hedgehog signaling specifically in bone-forming osteoblasts are largely unknown. Here, we identified SLIT and NTRK-like protein-5(Slitrk5), a transmembrane protein with few identified functions, as a negative regulator of hedgehog signaling in osteoblasts. Slitrk5 is selectively expressed in osteoblasts and loss of Slitrk5 enhanced osteoblast differentiation in vitro and in vivo. Loss of SLITRK5 in vitro leads to increased hedgehog signaling and overexpression of SLITRK5 in osteoblasts inhibits the induction of targets downstream of hedgehog signaling. Mechanistically, SLITRK5 binds to hedgehog ligands via its extracellular domain and interacts with PTCH1 via its intracellular domain. SLITRK5 is present in the primary cilium, and loss of SLITRK5 enhances SMO ciliary enrichment upon SHH stimulation. Thus, SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts that may be attractive as a therapeutic target to enhance bone formation.

Alternate JournalNat Commun
PubMed ID34326333
PubMed Central IDPMC8322311
Grant ListDP5 OD021351 / OD / NIH HHS / United States
R01 AR075585 / AR / NIAMS NIH HHS / United States
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