Differentiation and Disease

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.

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Cochella Group

The different cell types in a multicellular organism are the end result of exquisitely orchestrated genetic programs thought to be driven mostly by combinations of transcription factors expressed with very high spatial and temporal specificity. More recently, miRNAs have been recognized as having the potential to be integral parts of such genetic programs and thus play a widespread role in generating cell-type diversity during development. We are dissecting the function of miRNAs and testing their roles in cell-type differentiation in the worm C. elegans, as it provides us with a well defined developmental system with a large and diverse genetic and molecular biology toolbox.

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Haubensak Group

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.

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Keays Group

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 ? and ?-tubulins. The importance of this multi-gene family is exemplified by the finding that mutations in the ?-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.

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Obenauf Group

Metastasis is the colonization of distant organs by circulating tumor cells. It represents the final stage of cancer progression, and causes 90% of cancer related deaths. Current treatment regimen frequently fail to provide durable clinical responses, because cancer cells re-wire various tightly regulated cellular processes that make them extremely efficient in utilizing survival signals, evading immune-mediated killing, and adapting to new environments. The Obenauf group dissects these metastasis-related cellular programs in cell culture systems and mouse models, and integrates the obtained results with clinical data. The goal is to understand the mechanistic determinants of tumor formation, metastatic colonization, and drug resistance to identify new cancer cell vulnerabilities and drug targets.

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Pauli Group

Embryogenesis – the development of a single cell into a fully patterned organism - is one of the most fundamental yet complex biological processes. While most of the signaling pathways and genes that are essential for embryonic development had generally been assumed to be known, recent studies discovered that many regions outside of the annotated protein-coding open reading frames (ORFs) are translated, raising the intriguing possibility that new embryonic regulators remain to be identified. While some of these translated regions are predicted to encode short proteins/peptides whose conservation often suggests functional importance, others lack signatures of protein conservation and might have regulatory roles. The Pauli lab investigates the functions of these newly discovered translated regions in the context of embryonic development, using zebrafish as a model organism.  

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Pavri Group

Antibodies form the basis of all long term serum immunity against pathogens and thus lie at the very core of a healthy immune response. The process by which the immune system generates the vast repertoire of pathogen-specific antibodies from a limited set of genes is called antibody gene diversification. This diversity occurs in the germline of the antibody-encoding Immunoglobulin (Ig) locus of B lymphocytes via a complex interplay of transcriptionally-coupled focused mutagenesis, non-homologous recombination and DNA repair. The Pavri group investigates the molecular mechanisms regulating this phenomenon by utilizing a broad combinatorial approach involving mouse genetics, molecular immunology, RNAi-based screening, cellular imaging and genomics.

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Peters Group

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.

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Stark Group

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.

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Tanaka Group

Organ and appendage regeneration involves a response to injury that results in loss of adult phenotype, and the generation of proliferative progenitors that  coordinately pattern and differentiate to appropriately regenerate only the missing part.  We use axolotl appendage regeneration and mammalian organoid systems to understand the basis of tissue formation.  In the axolotl, we have mapped the cells that are responsible for limb regeneration and spinal cord regneeration  We have also identified a number of signalling pathways that coordinate their regeneration.  The factors that confer the ability of these cells to enter developmental programs of organogenesis at the onset of regeneration and the evolution of regeneration are of future interest.

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Zuber Group

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.

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