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Bone Morphology is Regulated Modularly by Global and Regional Genetic Programs

View ORCID ProfileShai Eyal, Shiri Kult, Sarah Rubin, Sharon Krief, Kyriel M. Pineault, View ORCID ProfileDeneen M. Wellik, View ORCID ProfileElazar Zelzer
doi: https://doi.org/10.1101/324293
Shai Eyal
1Weizmann Institute of Science, Department of Molecular Genetics, Rehovot 76100, Israel
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Shiri Kult
1Weizmann Institute of Science, Department of Molecular Genetics, Rehovot 76100, Israel
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Sarah Rubin
1Weizmann Institute of Science, Department of Molecular Genetics, Rehovot 76100, Israel
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Sharon Krief
1Weizmann Institute of Science, Department of Molecular Genetics, Rehovot 76100, Israel
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Kyriel M. Pineault
2University of Michigan Medical School, Department of Cell & Developmental Biology, Ann Arbor, MI 48109, USA
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Deneen M. Wellik
2University of Michigan Medical School, Department of Cell & Developmental Biology, Ann Arbor, MI 48109, USA
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Elazar Zelzer
1Weizmann Institute of Science, Department of Molecular Genetics, Rehovot 76100, Israel
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ABSTRACT

During skeletogenesis, a variety of protrusions of different shapes and sizes develop on the surfaces of long bones. These superstructures provide stable anchoring sites for ligaments and tendons during the assembly of the musculoskeletal system. Despite their importance, the mechanism by which superstructures are patterned and ultimately give rise to the unique morphology of each long bone is far from understood. In this work, we provide further evidence that long bones form modularly from Sox9+ cells, which contribute to their substructure, and from Sox9+/Scx+ progenitors that give rise to superstructures. Moreover, we identify components of the genetic program that controls the patterning of Sox9+/Scx+ progenitors and show that this program includes both global and regional regulatory modules.

Using light sheet fluorescence microscopy combined with genetic lineage labeling, we mapped the broad contribution of the Sox9+/Scx+ progenitors to the formation of bone superstructures. Additionally, by combining literature-based evidence and comparative transcriptomic analysis of different Sox9+/Scx+ progenitor populations, we identified genes potentially involved in patterning of bone superstructures. We present evidence indicating that Gli3 is a global regulator of superstructure patterning, whereas Pbx1, Pbx2, Hoxa11 and Hoxd11 act as proximal and distal regulators, respectively. Moreover, by demonstrating a dose-dependent pattern regulation in Gli3 and Pbx1 compound mutations, we show that the global and regional regulatory modules work coordinately. Collectively, our results provide strong evidence for genetic regulation of superstructure patterning that further supports the notion that long bone development is a modular process.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 16, 2018.
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Bone Morphology is Regulated Modularly by Global and Regional Genetic Programs
Shai Eyal, Shiri Kult, Sarah Rubin, Sharon Krief, Kyriel M. Pineault, Deneen M. Wellik, Elazar Zelzer
bioRxiv 324293; doi: https://doi.org/10.1101/324293
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Bone Morphology is Regulated Modularly by Global and Regional Genetic Programs
Shai Eyal, Shiri Kult, Sarah Rubin, Sharon Krief, Kyriel M. Pineault, Deneen M. Wellik, Elazar Zelzer
bioRxiv 324293; doi: https://doi.org/10.1101/324293

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