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A recipe for mouse ribs

A simple computation models how cells make decisions when developing the ribcage of a mouse embryo...


In animal embryo development, ribs grow from the spinal chord towards the chest. In fish, that growth stops leaving an open chest cavity. But in land animals, like ourselves, cartilage continues to form at the tips of the ribcage and connects each rib to become the breastbone or sternum. Now the entire area of critical organs are enclosed in the 'chest cavity.' The sternum is created from the sides of the embryonic mesoderm layer, while ribs and vertebrae arise from embryonic somites.

In the journal eLife, first authors Jennifer Fogel from the University of Southern California (USC) along with Daniel Lakeland from Lakeland Applied Sciences, reveal how they observed and examined the development of mice vertebrate ribcages to recognize a pattern in how bone cells are influenced to make differentiation decisions.

In the study, the authors describe a simple computation that models the choices cells make while the ribcage is developing. Some cells become the bony section of each rib connected to the spine, while other cells form the cartilage tip of each rib that joins to become the sternum. Understanding this process required the team to integrate the effects of cell growth, cell death, and cell communication into their computational tool in order to gain insights into how the skeleton completes the rib cage.

Using their calculations, the scientists identified how differences in levels of the protein called Hedgehog (Hh) affect bone tissue formation. High levels of Hh biased the cells towards becomming bone. But Hh drops off in production as bone cells move further and further from the midline of the back. Bone cells become cartilage as they reach the rib tips.
"Our study suggests that regardless of whether an embryo gives rise to a large elephant or a small mouse, the rib skeleton has already organized itself while the embryo is smaller than a grain of rice. In addition, the modeling approach we developed can be used to understand the challenges of building new tissues in adults after injury."

Francesca V Mariani PhD, Assistant Professor. Stem Cell Biology and Regenerative Medicine, Principal Investigator, the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC.

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.

Authors: Jennifer L Fogel Daniel L Lakeland In Kyoung Mah Francesca V Mariani. In Kyoung Mah from USC also contributed to the study.

Funding came from the University of Southern California, and NIH NIAMS. Fogel was supported by a postdoctoral fellowship from the California Institute for Regenerative Medicine.

Ninety-five percent of this work was supported by $1,727,898 in U.S. federal funding from a National Institutes of Health grant (R01 NS067213-01A1). Five percent of the project was funded by $10,000 from two non-U.S. sources: a DIRAMS grant funded by the South Korean government (50590-2017), and the National Natural Science Foundation of China.

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Dec 1, 2017   Fetal Timeline   Maternal Timeline   News   News Archive




Mouse rib cage stained to show cartilage (blue) and bone (red). Image credit: Francesca Mariani.


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