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 
