UMMS Affiliation

Division of Rheumatology, Department of Medicine

Publication Date

2021-07-29

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Cell Biology | Developmental Biology

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.

Keywords

Bone development, Membrane proteins, Morphogen signalling

Rights and Permissions

Copyright © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

DOI of Published Version

10.1038/s41467-021-24819-w

Source

Sun J, Shin DY, Eiseman M, Yallowitz AR, Li N, Lalani S, Li Z, Cung M, Bok S, Debnath S, Marquez SJ, White TE, Khan AG, Lorenz IC, Shim JH, Lee FS, Xu R, Greenblatt MB. SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts. Nat Commun. 2021 Jul 29;12(1):4611. doi: 10.1038/s41467-021-24819-w. PMID: 34326333; PMCID: PMC8322311. Link to article on publisher's site

Journal/Book/Conference Title

Nature communications

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

PubMed ID

34326333

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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