My lab studies the role of endosomal trafficking during Dpp (Decapentaplegic) morphogenetic signaling. We focus on four issues, with a strong quantitative emphasis. One of them is the study of the role of different populations of endosomes during signaling and mitosis. The others relate to the physics of Dpp endosomal trafficking, gradient formation and interpretation, as well as the physics of gradient formation during tissue growth.

The final goal is to have a comprehensive understanding of patterning and growth during development from a molecular, cell biological and physical perspective.

Asymmetric cell division is the process by which a cell divides to give birth to two cells that are different in fate. This is a fundamental process for the generation of cell diversity during development and for the self-renewal of stem cells. Asymmetric cell division relies first on the establishment of cell polarity and asymmetric localization of cell fate determinants. Subsequently, the mitotic spindle must be positioned properly, so that at division the cell fate determinants are unequally segregated between the two daughter cells.

The regulation and interconnection of the signaling cascades underlying these events remain elusive. The goal of our research is to identify and characterize new factors required for polarity and spindle positioning. We use the C. elegans one-cell embryo as a model system and a combination of genetics, microscopy, biochemistry and functional genomics. Since the molecular mechanisms underlying asymmetric cell division are conserved, our studies will improve our understanding of this process not only in C. elegans but also in other systems, in particular in the control of the self-renewal of normal and cancer stem cells.

The long-term goal of our research is to understand cancer at the molecular level and use this knowledge to develop novel cancer therapies. This is a very ambitious goal. Yet, because it is shared by many laboratories world-wide, there is considerable progress and hope for new effective therapies in the coming decades.

One of the main research areas in our lab concerns the activation of DNA damage checkpoint pathway, as a universal difference between cancer and normal tissues. We also concentrate on the analysis of the DNA double strand break (DSB) checkpoint, as well as on the mechanisms by which cells respond to DNA replication stress.

We use a broad range of techniques to address these questions, such as analysis of genomic instability of human cancer specimens, analysis of the molecular function of DNA damage checkpoint and DNA replication checkpoint protein in human cells, live cell microscopy, protein biochemistry and protein crystallography. This multidisciplinary approach has allowed us, among other things, to propose a mechanism by which the protein 53BP1 recognizes DNA double strand breaks in mammalian cells.

The difference that we identified as distinguishing cancer cells from normal ones relates to the state of activation of the DNA damage checkpoint pathway. What we found is that while in the majority of normal cells the DNA damage checkpoint pathway is not active (because in normal cells the DNA is not damaged), in human precancerous and cancerous tissues, the DNA damage checkpoint pathway is constitutively activated.

We study mechanisms of epigenetic regulation of animal-cell proliferation and differentiation. To this end, our investigations derive from the study of a key regulator of human-cell proliferation that is also implicated in embryonic stem cell maintenance and cancer. This protein, called HCF-1 (herpes simplex virus host-cell factor-1), binds to many promoters indirectly by recognizing site-specific DNA-binding proteins and recruits histone-modifying activities for activation and repression of transcription.

Our recent studies in human cells have revealed important links between HCF-1 and the E2F family of cell cycle regulators. E2F transcriptional regulators control human-cell proliferation by repressing and activating the transcription of genes required for cell-cycle progression, particularly the S phase.

Our results suggest that HCF-1 proteins possess conserved roles in the regulation of cell division and mitotic histone phosphorylation.

Our overall aim is to understand how form develops in the embryo, how it is maintained in the adult and how it is deregulated in diseases. The lab developed two major lines of research focusing on the role of the Gli proteins in development and in disease.

Normal development - We are investigating how the Gli transcription factors work to regulate cells performance in response to extracellular signs. Gli proteins are the effectors of Hedgehog signaling in many cell types and organs, but they may also act in response to other signals, such as FGF. Gli proteins overall function, the Gli code, is essential for interpreting the meaning of the signaling information. Our studies aim to clarify how these proteins determine cells’ fate. We are focusing on the role of Gli proteins in different, but related, aspects of animal development centred on neurogenesis.

Disease - Our research on the pattern formation of early embryos has led us to study two types of diseases:

• pathologies due to cell loss, such as Parkinson’s disease: we investigate the role and potential of Gli proteins to specify dopaminergic cell fate and to expand appropriate stem cell populations,
• pathologies due to non-homeostatic increase in cell number, such as cancer: following our work showing that sustained Hedgehog-Gli signaling is required for human basal cell carcinomas growth and survival, we continue to investigate the participation of Gli proteins in such tumors, with the goal of developing a rational, wide-spectrum anti-cancer therapy.