A minimally sufficient model for rib proximal-distal patterning based on genetic analysis and agent-based simulations

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Abstract

For decades, the mechanism of skeletal patterning along a proximal-distal axis has been an area of intense inquiry. Here we examine the development of the ribs, simple structures that in most terrestrial vertebrates consist of two skeletal elements- a proximal bone and a distal cartilage portion. While the ribs have been shown to arise from the somites, little is known about how the two segments are specified. During our examination of genetically modified mice, we discovered a series of progressively worsening phenotypes that could not be easily explained. Here, we combine genetic analysis of rib development with agent-based simulations to conclude that proximal-distal patterning and outgrowth could occur based on simple rules. In our model, specification occurs during somite stages due to varying Hedgehog protein levels, while later expansion refines the pattern. This framework is broadly applicable for understanding the mechanisms of skeletal patterning along a proximal-distal axis.

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Jennifer L Fogel

Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
Daniel L Lakeland

Lakeland Applied Sciences LLC, Altadena, United States

Competing interests
The authors declare that no competing interests exist.
In Kyoung Mah

Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
Francesca V Mariani

Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, United States

For correspondence
fmariani@usc.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-1619-8763

Funding

California Institute for Regenerative Medicine (Postdoctoral Fellowship)

Jennifer L Fogel

University of Southern California

Jennifer L Fogel
Daniel L Lakeland
In Kyoung Mah
Francesca V Mariani

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#11152) of the University of Southern California.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.