Group of Developmental Morphogenesis

Beginning with the fertilized egg, the human body is constructed according to complex developmental processes, which operate under the control of programs written in the genome. We are studying the molecular mechanisms of the programs that control positional specification and position-specific morphogenesis during vertebrate limb development.

Genetic system controlling the position of limb bud

The tetrapod limb develops from the limb bud, which is induced at a specific position within the lateral plate mesoderm. Fgf10 is a signaling molecule whose function is essential for the limb bud formation. As Fgf10 expression begins in the presumptive area of the limb bud in the lateral plate mesoderm, we believe that the genetic system determining the position of limb bud directly controls the expression of Fgf10. In order to elucidate the regulatory mechanism, we have sought to identify the cis-regulatory element in the Fgf10 gene that is responsible for limb-specific expression in a transgenic mouse system. We found that three independent enhancers are responsible for initiation of Fgf10 expression in the presumptive limb field (R2), limb bud mesenchyme specific expression (R3) and maintenance of the expression through tissue interaction (R1). The cis elements in each enhancer have been identified, and we are currently identifying the transcription factors that function through the cis elements.
We are also interested in the evolution of the cis element during acquisition of the fin and evolution of the limb from the fin. We found that the R3 enhancer is present in Fgf10 of the cartilaginous fish, i.e., it must have arisen during evolution from finless jawless vertebrates. In addition, the R2 enhancer is missing in urodele amphibians, whose limb bud formation occurs at a far later stage than in the amniote embryo. Thus, the cis element in Fgf10 plays a crucial role in the diversification of the developmental system.

Hox genes control the limb cartilage pattern formation

Hox was first identified as a gene system determining positional identity along the anteroposterior axis during fruit fly development; it was later realized that a similar process occurs in vertebrates. We have reported that Hox genes also control position-specific morphogenesis of limb cartilage. Hox proteins are transcription factors that regulate position-specific expression of downstream target genes involved in position-specific control of cell adhesion, cell differentiation, and cell division. We are trying to isolate such genes using Hox knockout mice; some candidates have already been identified. Using these candidate target genes, we are studying how each Hox protein regulates the expression of its target genes.

Lab members