Dissertation Improvement: Elucidation of Hominid Vertebropelvic Evolution via Observational and Experimental Analyses of Murine Embryogenetics and Avian Developmental Biology

Kent State University, Kent OH

Investigators

Abstract

The embryology and development of the human vertebral column and pelvis are important in a broad range of contexts, including the etiology and causation of human birth defects, as well as the normal growth and maturation of the trunk, pelvis, and lower limb. Other important areas include the identification of factors that affect overall pelvic form in ways that impact obstetric difficulty and success. The anatomy of this region is also central to our understanding of the process of human and primate evolution, especially the appearance and progressive adaptation of the lower limb to upright walking. A complete understanding the vertebral and pelvic embryology ultimately requires knowledge of their developmental genetics. In this research, three embryological models of the developmental progress of the sacrum, including a number of its important special features, such as segmental fusion, will be examined. Each makes different predictions with respect to the tempo and mode of sacroiliac change. Resolving which model is most accurate (and therefore most likely to be correct) requires a more thorough knowledge of this region's developmental biology. Given the rarity of specimens and the prolonged developmental period of primates (and other practical prohibitions as well), the researchers will perform skeletal analyses of mouse gene "knockouts" and examine chick embryological manipulations. These are effective alternatives to direct examination of the embryological processes in primates and humans. Recent gene knockouts (i.e., the targeted deactivation of a specific gene's normal activity) include a number that have a profound effect on normal spine and pelvis development. These include Pitx1, Emx2, Fgf10, and Fgf4-Fgf8. Examination of the role of each can potentially illuminate central aspects of the developmental (and thereby naturally selected) "units" of the pelvic girdle and lower limb, as well as clarify the developmental relationships between the pelvic bones and sacrum. High resolution microCT scans of mice in which one of these genes has been "deactivated" will be examined. Quantitative measures will be made of the three dimensional structure of the pelvis and spine in each mutant using NIH software. Identical procedures will be applied to normal mice of the same strain. In addition, fate maps of embryological tissues of the sacrum and pelvis will be examined in chicks in which transplantations of quail donor cells have been introduced. This technique has not been used previously to answer questions about vertebropelvic development in humans. Combining these data (mouse gene knockouts and avian embryological manipulation) will enhance our understanding of a crucially important and relatively new avenue of human evolutionary research, i.e., determining the biological effects of key genes (and their downstream targets) in shaping the human frame. As understanding of the human genome unfolds, anthropologists must keep pace by improving our understanding of those genes which are central to human anatomy and evolution. In addition, broader issues of evolution in limbed animals such as limb loss in snakes and whales, as well as the evolution of variations of spinal segmentation promise to be further illuminated by this research. A substantial proportion of the work to be conducted involves support and maintenance of the microCT laboratory at the Northeast Ohio Universities College of Medicine (NEOUCOM). This facility is vital to a variety of current clinical projects involving bone and cartilage growth and development. The work will also enhance world-wide scientific cooperation as a number of the mutant specimens that will be examined have been developed in Europe, Japan, Canada, as well as the United States. Agreements for the exchange of data derived from these specimens have already been arranged. NSF support will allow at least one anthropology graduate student to complete the Ph.D. Finally, enhancement of our understanding of these fundamental developmental processes is very likely to prove vital in furthering our capacity to diagnose and treat serious embryological defects.