.: University of Freiburg  .: Faculty  .: Biologie I  .: Developmental Biology
Dr. Giorgos Pyrowolakis
Institut für Biologie I
Lehrstuhl für Entwicklungsbiologie

BMP-Mediated Transcriptional Repression in Drosophila

Metazoan development critically depends on a handful of conserved signaling pathways that mediate cellular communication. Ligands of the TGF-beta/BMP superfamily of signaling molecules activate an evolutionary conserved signal transduction pathway resulting in transcriptional changes in the nucleus of the signal receiving cell. Our recent studies on the nuclear interpretation of the morphogen Decapentaplegic, a member of the BMP family in Drosophila melanogaster, uncovered a branch of the BMP-signaling pathway that results in direct repression of key developmental genes. BMP-mediated gene repression is mediated by small silencer elements (SE) in the cis-regulatory regions of target genes; these elements consist of Smad binding sites in a specific arrangement that instructs the recruitment of a co-repressor to the DNA/Smad complex. The overall aim of our work is to obtain a global view of the properties and the biological effects of this novel signal-induced gene repression branch. With Drosophila as our main model system and a combination of genetic, biochemical and cell culture-based methods we are currently focusing on following aspects:

1. Identify and analyze genes that are regulated by the pathway.
The simplicity of the SE and the establishment of a rigorous consensus sequence for this element will be exploited in genome-wide in-silico screens to identify target genes of this branch of the pathway. These genes are expected to be effectors of the BMP-signaling pathway and their characterization in vivo will help to unravel the variety of biological consequences of BMP-signaling. This approach already culminated in the identification of evolutionary conserved BMP target genes that are probably involved in modulating the activity of BMP-signaling itself as part of a regulatory feed-back loop. The exact mechanism by which these proteins shape the activity of BMP-signaling during development will be studied both in Drosophila and in zebra fish.

2. Identify and analyze components that, in addition to the well-characterized core components of the signal transduction pathway, are involved in signal-mediated gene regulation.
To this end, Drosophila cell culture assays that recapitulate BMP-mediated gene regulation in a quantitative manner were established and combined with a high-throughput genome-wide RNAi-based technology (in collaboration with M. Boutros, DKFZ, Heidelberg). The approach aims at the identification of factors that are in work to discriminate between transcriptional activation and repression by the BMP pathway as well as factors that mediate cross talk between the BMP-signaling pathway and other developmental signaling pathways.





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 .: University of Freiburg  .: Faculty  .: Biologie I  .: Developmental Biology