SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts

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 () and Matthew B. Greenblatt ()
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Jun Sun: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine
Dong Yeon Shin: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine
Mark Eiseman: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine
Alisha R. Yallowitz: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine
Na Li: Xiamen University
Sarfaraz Lalani: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine
Zan Li: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine
Michelle Cung: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine
Seoyeon Bok: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine
Shawon Debnath: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine
Sofia Jenia Marquez: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine
Tommy E. White: Tri-Institutional Therapeutics Discovery Institute
Abdul G. Khan: Tri-Institutional Therapeutics Discovery Institute
Ivo C. Lorenz: Tri-Institutional Therapeutics Discovery Institute
Jae-Hyuck Shim: University of Massachusetts Medical School
Francis S. Lee: Weill Cornell Medical College
Ren Xu: Xiamen University
Matthew B. Greenblatt: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24819-w

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