Research

Decades of mouse genetics have identified genes and pathways that are essential for normal limb development.

However loss-of-function mutations in the mouse often result in non-viable offspring with phenotypes affecting all four limbs and do not accurately reproduce the variety of forms seen in nature or in human malformations. The future of developmental genetics and evolution, as two sides of the same coin, will largely focus on how subtle variations of timing, pattern, and quantity of these genes mold the differences both within and between species. Pairing the technical strengths of model systems with the unique morphologies of non-model organisms stands to transform our understanding of how regulation of critical and conserved genetic networks functions to shape developing organisms. In an effort to tap into the naturally occurring

genetic “selection experiment” that has been underway since the origin of the vertebrate limb, our lab studies the Lesser Egyptian Jerboa, Jaculus jaculus, as a new experimental system. The jerboa is closely related to the laboratory mouse, enabling direct comparison to an established model system with very similar genomic architecture and developmental staging, and yet with extremely divergent limb morphology. This desert-adapted bipedal rodent has normally proportioned forelimbs with five fingers and extraordinarily long hindlimbs with three toes on its disproportionately large feet, fused metatarsals, and an absence of foot muscles.

The goal of our research program is to capitalize on extreme divergence in the jerboa limb as a means to explore the broader and profoundly important relationship between gene regulatory landscapes and phenotypic malleability.

Specific projects:

How are the correct numbers and
positions of the digits established?

Loss of the first and fifth toes in the jerboa occurs through an expansion of the cell death mechanism that normally separates the fingers and toes. The death of pre-chondrogenic cells at the tips of these toes is associated with expanded expression of two genes known to regulate cell death in the limb, Bmp4 and Msx2. We are using transgenic and targeted gene replacement approaches to identify the gene regulatory control elements that are sufficient to replicate jerboa-like digit loss in the mouse. The success of this experimental approach will also set the stage to reveal mechanisms of malleability across many loci and phenotypes.

What mechanisms determine the size and relative
proportions of individual skeletal elements?

The largest contributor to the rate of skeletal elongation is the cell volume increase of terminally differentiated chondrocytes in the growth plate at the end of a long bone. We are working to understand the mechanisms that control cell size, and thus skeletal growth rate, by identifying genes that are expressed differently in the jerboa metatarsal growth plate compared to mouse. In addition to providing insight on how the body proportion is shaped, such pathways are potential therapeutic targets for growth plate-specific treatment of skeletal growth asymmetry in humans.

How does a bone fuse with its adjacent neighbor?
How is bone reshaping controlled?

Even human skeletons are more than static structural elements that support our bodies. Your bones are constantly being replaced and reshaped by osteoclasts that chew up old bone and osteoblasts that lay down fresh bone. In the juvenile jerboa foot, there is a burst of osteoclast activity that resorbs bone at the interface of adjacent metatarsals and osteoblast activity that lays bone down to form a cylinder around a single marrow cavity. We are working to identify the mechanisms that control the localized activity of these two cells types and to understand the mechanical advantage of bone fusion in evolution. Additionally, these findings will shed light on the process of osteoporosis and developmental disorders of bone formation.

When a genetic alteration changes the morphology of a
tissue, how does that affect the development of
integrated tissue types?

Jerboas are born with foot muscles that are attached by tendons to bone and are properly innervated. Within the first week after birth, the metatarsals rapidly elongate, the muscles in the feet degenerate, and the tendons expand. We are working to understand the mechanisms of muscle loss and tendon expansion and to test the hypothesis that these phenotypes are secondary effects of stretch forces due to accelerated metatarsal elongation. Furthermore, we seek to understand the fate of neurons when their target muscles are lost. Together, these results will illustrate the extent to which morphological change results from a cascade of tissue interactions.

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READ KIM'S BIO

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OUR LATEST FINDINGS

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WANT TO KNOW MORE ABOUT JERBOAS?

Jerboas are remarkably adapted to their native desert environment yet very amendable to domesticated life.