Research Overview
Contributions of the Pbx Family of Hox Cofactors to Mammalian Development and Organogenesis
We have generated knock-out mice to study the developmental contributions of human proto-oncogenes. Our focus is on the biological functions of Pbx1, a homeodomain protein originally identified as the product of an oncogene in childhood leukemias. Pbx1 is the vertebrate homologue of Drosophila extradenticle (EXD). As heterodimers with other homeodomain proteins, Pbx1 and its related family members Pbx2 and Pbx3 simultaneously interact and bind DNA with Hox proteins, thereby acting as Hox-cofactors. We have generated three knock-out mouse strains for Pbx1, Pbx2 and Pbx3. These have led us to unveil the functions of Pbx proteins in development and organogenesis. Our work shows that Pbx1 is required for normal skeletal development in vertebrates and defines Pbx1-dependent domains, such as the axial skeleton and proximal limb structures. Using cell lines generated from Pbx1 knock-out embryos we have also shown that Pbx1 is required for normal cellular proliferation. In sum, using intact animal models we have demonstrated a role for Pbx1 in multiple developmental programs and revealed a novel function for Pbx1 in coordinating the extent and timing of cellular proliferation with terminal differentiation. Because multiple organ systems (musculoskeletal, hematopoietic, vascular, spleen, pancreas) are severely affected in these knock-out mice, they represent a rich resource for studying relationships between developmental genetic pathways and molecular pathology of organ systems in vertebrates. We are using a variety of genetic approaches, bridging the gap between cloning/gene discovery and gene function, and focus on the study of normal developmental pathways and their perturbations in murine model systems and human disease. In particular, our efforts are directed towards a deep understanding of the roles of Pbx proteins in musculoskeletal development and in angiogenesis. Future research goals also include cloning of new genes involved in malformations of the axial skeleton through the analysis of mouse mutant phenotypes. E-mail lis2008@med.cornell.edu For more information, please visit: http://www.cornellcelldevbiology.org/selleri
