The mammalian genome with its ~25,000 genes contains the genetic information for directing the development of a totipotent zygote into a multicellular organism. As the function of only a minority of these genes is currently known, it is an important scientific challenge to identify and characterize key genes and their molecular mechanisms which contribute to embryonic development, cell lineage differentiation and cell function in health and disease. At the IMP, the groups in Differentiation and Disease combine their expertise to investigate these differentiation processes in several animal model and human cell systems. By taking advantage of the power of genetics combined with molecular biology, biochemistry, genome-wide sequencing and high-throughput siRNA approaches, we provide novel insight into the molecular functions of regulatory factors, effector molecules and structural proteins in embryogenesis, cell division, hematopoiesis, leukemia development and neurodevelopmental disease.
Busslinger Group
Acquired immunity against pathogens depends on the differentiation of B and T lymphocytes from hematopoietic stem cells, which is controlled by a multitude of transcription factors. The Busslinger group investigates the transcriptional control of early B and T cell development by using a combination of mouse transgenic, cell biological, molecular and high-throughput sequencing approaches. These studies have provided and will continue to provide important insight into the molecular mechanisms by which transcription factors control lymphocyte commitment and differentiation and, upon deregulation, contribute to the development of lymphoid tumors.
A single egg cell gives rise to the hundreds of cell types that make up complex organisms like ourselves. One way by which cells adopt new identities is asymmetric cell division: fate determinants – proteins, organelles, and other sub-cellular compartments – segregate to one of the two daughter cells during mitosis and cause a functional change. Cell polarity provides spatial control for asymmetric cell division, determining where fate determinants will go. The Cowan group is studying how polarity domains at the cell cortex convey spatial information to the inside of the cell to achieve global organization of fate determinants in C. elegans embryos.
A central biomedical goal is to understand how genes control brain functions in health and disease, and how drugs modulate these brain functions to ameliorate psychological conditions. While the molecular mechanisms by which genes and drugs control neural activity at the cellular level have been worked out in great detail, the circuit mechanisms by which this translates into behavior changes have not yet been resolved. To this end, we investigate gene and drug effects on the activity of specific emotion control circuits (identified by genetic circuit dissection) and how these changes in activity modulate emotional states and behavior, ultimately linking molecular events to behavioral output.
The formation of the human brain is a remarkable phenomenon. Billions of neurons proliferate, migrate and differentiate creating what is arguably, the most complex structure on the planet. The developmental processes that underpin this biological construction are highly dependent on microtubules and their constituents, the α and β-tubulins. The importance of this multi-gene family is exemplified by the finding that mutations in the α-tubulin gene TUBA1A cause the devastating “smooth brain” disease, lissencephaly. The Keays group is employing the mouse to gain insight into the role of different tubulin genes in neurodevelopment, and the mechanisms by which mutations in these genes cause disease.
To pass the genome from one generation to the next, human cells first generate two copies of each of their 46 chromosomes and then segregate these copies from each other during mitosis, so that two genetically identical daughter cells can be formed. Defects in these processes are frequently observed in human tumors and are thought to contribute to the evolution of malignant cells with abnormal genomes. Conversely, pharmacologic inhibition of chromosome segregation is used as a therapeutic strategy to treat cancer patients. The Peters group studies the molecular mechanisms of chromosome segregation in human cultured cells and several animal model systems.
Animal development is determined by transcriptional programs that determine the differentiation and function of different cell types. These programs or networks are defined by the dynamic interplay of transcription factors and cis-regulatory sequences (enhancers). The Stark group uses experimental and computational techniques to study how gene regulatory information is encoded in the genome sequence. Using ChIP-Seq, in vivo and in vitro enhancer screens, sequence analyses, and machine learning, we aim at “cracking” the regulatory code, predicting enhancer activity from the DNA sequence, and to understand how transcriptional networks define cellular and developmental programs.
Acute myeloid leukemia (AML) is an aggressive cancer of abnormal white blood cells. AML develops as a result of accumulating mutations that promote uncontrolled growth and block cell-fate programs in myeloid progenitors. Over 100 mutations have been linked to AML - and this genetic heterogeneity complicates the search for effective targeted therapies. Our approach combines genetically defined mouse models and in-vivo RNAi to identify key genes and pathways in AML development, disease maintenance and therapy response. To further evaluate putative drug targets, we apply novel Tet-regulatable RNAi systems, which enable to study target inhibition in established cancers and normal tissues.
Zuber, J., et al (2011). Toolkit for evaluating genes required for proliferation and survival using tetracycline-regulated RNAi. Nat Biotechnol. 29(1):79-83
