Mechanisms of phenotypic malleability in the vertebrate limb
Questions That Excite Us
Our long femur and tibia give us our stride length, and our comparably short fingers allow us to grasp and manipulate objects with extraordinary dexterity. Yet each of the bones of our arms and legs formed in the embryo as tiny rods of similar size. How does each developing skeletal element elongate at a different rate and know when to stop to achieve the appropriate adult proportions?
Loss-of-function mutations in mice commonly cause phenotypes affecting all four limbs indicating most of the genes required for limb development function in both the arms and legs. However, many animals have very different fore and hindlimbs, and 92% of human congenital limb defects specifically affect the arms or legs but not both. How are shared genes deployed differently in the two pairs of limbs?
How We Answer These and More
The jerboa is a bipedal rodent with "normal" arms and unique legs that allow it to bound through the deserts of Africa and Asia. It has extraordinarily long hindlimbs (particularly the feet), fused metatarsals, three toes, and no foot muscles. My lab capitalizes on these specialized features of the jerboa hindlimb, the strengths of mouse genetic engineering, and the close evolutionary relationship of the two species to understand the development and evolution of limb form and function. We take an integrative approach to investigate differences between the mouse and jerboa at the level of cells, tissues, and gene expression in the limb musculoskeletal system. This gives us a deeper understanding of fundamental developmental events including mechanisms of growth and tissue maintenance that are common to all animals but that are malleable within and between species. Therefore, in addition to shedding light on the remarkable mechanisms that generate the diversity of life, we are gaining insight into developmental events that parallel human birth defects and musculoskeletal injuries
Once we have strong evidence of a putative role for particular gene(s), our goal is to replace the mouse genomic DNA with a large fragment of the same location in the jerboa genome. This will allow the expression of that gene in the mouse to be controlled in the same way it is controlled in the jerboa. With these mice, we will be able to identify sequences that are sufficient to give the mouse a "jerboa-like" hindlimb. Our broader goal from these studies is to identify gene regulatory elements that control where and when genes are used in limb development and that are responsible for the differences we see within and between species.