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Thm2 interacts with paralog, Thm1, and sensitizes to Hedgehog signaling in postnatal skeletogenesis

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Abstract

Mutations in the intraflagellar transport-A (IFT-A) gene, THM1, have been identified in skeletal ciliopathies. Here, we report a genetic interaction between Thm1, and its paralog, Thm2, in postnatal skeletogenesis. THM2 localizes to primary cilia, but Thm2 deficiency does not affect ciliogenesis and Thm2-null mice survive into adulthood. However, by postnatal day 14, Thm2−/−; Thm1aln/+ mice exhibit small stature and small mandible. Radiography and microcomputed tomography reveal Thm2−/−; Thm1aln/+ tibia are less opaque and have reduced cortical and trabecular bone mineral density. In the mutant tibial growth plate, the proliferation zone is expanded and the hypertrophic zone is diminished, indicating impaired chondrocyte differentiation. Additionally, mutant growth plate chondrocytes show increased Hedgehog signaling. Yet deletion of one allele of Gli2, a major transcriptional activator of the Hedgehog pathway, exacerbated the Thm2−/−; Thm1aln/+ small phenotype, and further revealed that Thm2−/−; Gli2+/- mice have small stature. In Thm2−/−; Thm1aln/+ primary osteoblasts, a Hedgehog signaling defect was not detected, but bone nodule formation was markedly impaired. This indicates a signaling pathway is altered, and we propose that this pathway may potentially interact with Gli2. Together, our data reveal that loss of Thm2 with one allele of Thm1, Gli2, or both, present new IFT mouse models of osteochondrodysplasia. Our data also suggest Thm2 as a modifier of Hedgehog signaling in postnatal skeletal development.

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Acknowledgements

We thank members of the KUMC Dept. of Anatomy and Cell Biology, the Jared Grantham Kidney Institute, and the UMKC Dept. of Oral and Craniofacial Sciences for helpful discussions. We thank Ms. Jing Huang of the KUMC Histology Core and Drs. Vivian and Larson of the KUMC Gene Targeting Institution Facility and acknowledge the support of these cores (Intellectual and Developmental Disabilities Research Center NIH U54 HD090216; KU Cancer Center NIH P30 CA168524; COBRE NIH P30 GM122731). This work was also supported by a KUMC Biomedical Research Training Fellowship, a pilot grant from the Kansas City Consortium on Musculoskeletal Diseases, and the National Institutes of Health (P20 GM14936; R01DK103033).

Funding

We thank members of the KUMC Dept. of Anatomy and Cell Biology, the Jared Grantham Kidney Institute, and the UMKC Dept. of Oral and Craniofacial Sciences for helpful discussions. We thank Jing Huang of the KUMC Histology Core and Drs. Vivian and Larson of the KUMC Gene Targeting Institution Facility and acknowledge the support of these cores (Intellectual and Developmental Disabilities Research Center NIH U54 HD090216; KU Cancer Center NIH P30 CA168524; COBRE NIH P30 GM122731). This work was also supported by a KUMC Biomedical Research Training Fellowship, a pilot grant from the Kansas City Consortium on Musculoskeletal Diseases, and the National Institutes of Health (P20 GM14936; R01DK103033).

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Authors and Affiliations

  1. Department of Anatomy and Cell Biology, Jared Grantham Kidney Institute, University of Kansas Medical Center, 3901 Rainbow Blvd., MS #3038, Kansas City, KS, 66160, USA

    Bailey A. Allard, Wei Wang, Tana S. Pottorf, Brittany M. Jack, Henry H. Wang, Luciane M. Silva, Damon T. Jacobs & Pamela V. Tran

  2. Department of Orthopedic Surgery, Medical Center, University of Kansas, Kansas City, KS, 66160, USA

    Jinxi Wang

  3. Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, MO, USA

    Hammad Mumtaz & Erin E. Bumann

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  1. Bailey A. Allard
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  2. Wei Wang
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  9. Jinxi Wang
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Contributions

BAA, WW, TSP, HM, BMJ, HHW, LMS, DTJ, JW, EEB, and PVT performed experiments and analyzed data. BAA, JW, EEB and PVT designed research. BAA, HM, JW, EEB and PVT wrote the manuscript. All authors read and accepted the final manuscript.

Corresponding author

Correspondence to Pamela V. Tran.

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The authors declare no conflict of interest.

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All animal procedures were conducted in accordance with KUMC IACUC and AAALAC rules and regulations.

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The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Allard, B.A., Wang, W., Pottorf, T.S. et al. Thm2 interacts with paralog, Thm1, and sensitizes to Hedgehog signaling in postnatal skeletogenesis. Cell. Mol. Life Sci. 78, 3743–3762 (2021). https://doi.org/10.1007/s00018-021-03806-w

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  • DOI: https://doi.org/10.1007/s00018-021-03806-w

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