One of the major discoveries in biology has been that many developmental pathways are conserved even between distantly related species. This was first realised by studying a class of genes - the Hox genes - that specify anterior-posterior (A/P) identities. Hox genes were originally discovered in Drosophila through their homeotic mutant phenotypes.

Hox genes, which are expressed in specific domains along the A/P body axis, assign different morphologies to individual segments. The transcription factors encoded by Hox genes regulate (so far largely unknown) sets of downstream genes in a segment-specific pattern. Only few targets have been identified, and almost none are known for the most informative group, the so-called realisator genes, which directly control morphogenetic processes such as rate and orientation of cell division or cell shape changes. Direct regulation by a Hox protein and functional relevance of this regulatory interaction in respect to segment morphology has only been demonstrated for a single realisator gene.

Work in my own group has expanded into two major directions. On the one hand, we have extended the identification and characterization of Hox downstream genes to the whole-genome level with the idea to quantitatively characterize Hox realisator genes to understand all aspects of the Hox dependent morphogenetic network. To this end we have performed a comparative microarray experiment using six of the eight Drosophila Hox genes, leading to the identification of hundreds of Hox downstream genes, with many of them being validated by in situ hybridizations on loss- and gain-of-function mutants. Interestingly, we found that that a large fraction of downstream genes encodes realisator functions, underlining the importance of this category of genes for the morphogenetic output. Focusing on these realisators, we could also provide a framework for the morphogenesis of the maxillary segment. Studying this group of Hox downstream genes will allow us in future to elucidate the morphogenetic function of most Hox genes.

The second major direction my lab is pursuing is to understand how Hox proteins acquire specificity in target gene selection. Using the regulation of rpr by Dfd as a model, we could show that Dfd works together with at multitude of transcriptional regulators to achieve regional specific activation of target genes. The newly identified co-factors themselves are known to play diverse roles during development and have spatially and temporarily restricted expression patterns. This suggests that Hox proteins acquire target specificity in vivo by interacting in a combinatorial fashion with cell- and/or tissue-specific transcription factors that also play important roles in other developmental processes. To test this hypothesis, we have developed a bioinformatics approach and have identified hundreds of Hox response elements in the Drosophila genome. The aim of this project is to verify and characterize these candidate Hox response elements in context of their enhancers and identify the corresponding trans-acting factors. These studies will significantly advance our understanding of how different Hox proteins regulate specific targets in vivo, shed light on the combinatorial logic of cofactor interactions and ultimately will help to answer the question how morphogenesis along the A/P axis is realized.

Personnel

Dr. Ingrid Lohmann

Group leader

Anette Habring-Müller

Technician

Petra Stöbe

PhD student

Daniela Bezdan

PhD student

Aurelia L. Fuchs

Ph.D. student

Zongzhao Zhai

PhD student

We are currently looking for undergraduate, diploma, PhD students and post-docs. Candidates with a strong background in developmental biology, experience in Drosophila genetics, molecular biology or bioinformatics should contact Ingrid Lohmann.

Key publications

• Lohmann I., McGinnis, N., Bodmer, N. and McGinnis W. (2002). The Drosophila Hox gene Deformed sculpts head morphology via direct regulation of the apoptosis activator reaper. Cell 110, 457-466.

• Lohmann, I and McGinnis, W. (2002). Hox genes: It's all a matter of context. Curr. Biol. 10, R514-R516.

• Lohmann, I. (2003). Dissecting the regulation of the Drosophila apoptosis activator reaper. Gene Expression Patterns 3, 159-163.

• Lohmann, I. (2006). Hox genes: Realising the importance of realisators. Curr. Biol. 16, R988-989.

• Hueber, S. D., Bezdan D., Henz, S. R., Blank M., Wu H. and Lohmann, I. (2007). Comparative analysis of Hox downstream genes in Drosophila. Development 134(2), 381-392.

• Stoebe, P., Stein, M. S., Habring-Müller, A., Fuchs, A. L., Hueber, S. D. and Lohmann, I. Combinatorial logic of Hox target gene regulation in Drosophila. (submitted)

• Hueber, S. D. and Lohmann, I. Shaping segments: Hox gene function in the genomic age. (invited review, BioEssays)