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SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts.

Nature communications (2021-07-31)
Jun Sun, Dong Yeon Shin, Mark Eiseman, Alisha R Yallowitz, Na Li, Sarfaraz Lalani, Zan Li, Michelle Cung, Seoyeon Bok, Shawon Debnath, Sofia Jenia Marquez, Tommy E White, Abdul G Khan, Ivo C Lorenz, Jae-Hyuck Shim, Francis S Lee, Ren Xu, Matthew B Greenblatt
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Influenza Hemagglutinin (HA) Peptide, ≥97% (HPLC)
Millipore
FLAG® Peptide, lyophilized powder
Sigma-Aldrich
Purmorphamine, A cell-permeable activator of Hedgehog signaling that induces osteoblast differentiation of multipotent mesenchymal progenitor cells C3H10T1/2 (EC₅₀ = 1 µM).
Millipore
EZview Red Anti-HA Affinity Gel
Sigma-Aldrich
Anti-Acetylated Tubulin antibody, Mouse monoclonal, clone 6-11B-1, purified from hybridoma cell culture