Previously we have shown an essential role for fibroblast growth factor FGF signaling during limb development by examining mice lacking genes that encode FGF ligands (Lewandoski et al. 2000 Nature Genetics 28:167, Sun et al 2000 Nature Genetics 25: 6 ). However, the complexity caused by Fgf gene redundancy has led us to consider approaching the problem by examining FGF receptor mutants leading to the insight that FGF signaling controls limb size (Verheyden JM et al 2005Development 132:4235). We are also studying the inter-relationship between FGF and BMP signaling. During normal limb development of animals that are born without webbed limbs, programmed cell death occurs in mesenchymal interdigit cells, thus removing them and sculpting the final digit pattern. The prevailing paradigm holds that BMP signaling in the interdigit region directly causes this programmed cell death. However, we have challenged this paradigm in our recent publication (Pajni-Underwood S. et al 2007 Development 134: 2359). By simultaneously inactivating the Bmp receptor gene, Bmpr1a as well as Fgf8 and Fgf4 specifically in the limb bud ectoderm, we have produced genetic evidence for a novel model in which the surface ectoderm must receive a BMP signal, resulting in down regulation of Fgfs which in turn induces apoptosis of the underlying mesenchyme (Pajni-Underwood S. et al 2007 Development 134: 2359). Thus we demonstrated that BMPs control programmed cell death indirectly, by regulating FGF signaling. We are extending these studies by studying the role of BMP and FGF signaling in various aspects of limb development using mouse lines that express Cre in specific region of the developing limb. For example the only way to test the hypothesis that BMPs act as direct effectors of cell death is to inactivate BMPs receptors only in the lineage that undergoes cells death, without affecting FGF expression in nearby cells. We have achieved this using new Cre lines which allow Cre-mediated gene inactivation in these lineages. With these lines are asking: are BMPs are direct effectors of normal programmed cell death? If not, how is programmed cell death controlled? If so, how do BMPs achieve this endpont?
| Mackem, Susan; Lewandoski, Mark (2009) Limb development takes a measured step toward systems analysis. Sci Signal 2:pe33 |
| Lewandoski, Mark; Mackem, Susan (2009) Limb development: the rise and fall of retinoic acid. Curr Biol 19:R558-61 |
| Lewandoski, M (2007) Analysis of mouse development with conditional mutagenesis. Handb Exp Pharmacol :235-62 |
| Pajni-Underwood, Sangeeta; Wilson, Catherine P; Elder, Cindy et al. (2007) BMP signals control limb bud interdigital programmed cell death by regulating FGF signaling. Development 134:2359-68 |
| Waters, Samuel T; Wilson, Catherine P; Lewandoski, Mark (2003) Cloning and embryonic expression analysis of the mouse Gbx1 gene. Gene Expr Patterns 3:313-7 |
