Ruiz i Altaba Lab
The role of the Gli proteins in development and in disease.
University of Geneva
University of Geneva Medical School
Department of Genetic Medicine and Development
1 rue Michel Servet
CH-1211 Geneva 4
Ruiz i Altaba, Ariel
The overall aim of our research is to understand how form develops in the embryo, how it is maintained in the adult and how it is deregulated in diseases. There are two major lines of research in the laboratory that focus on the role of the Gli proteins in development and in disease. 1- Normal development: We are particularly interested in understanding how the ‘zinc finger’ Gli transcription factors work regulating 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 in frog’s mesoderm embryo. Gli proteins overall function; the Gli code, is essential for interpreting the meaning of the signaling information. Our investigation aims to clarify how these proteins determine cells fate. This involves studying in depth the way these three proteins act, and also the way they interact with other factors as their actions depend on the context. We are focusing on the role of Gli proteins in different but related aspects of animal development. Our present work studies the role of Gli proteins in i- neural stem cells and their neurogenic niches of the embryo and adult mouse and human, ii- primary neurogenesis in the neural plate of frog embryos, iii- human tumors of different tissues, including brain, prostate, skin and breast. The methodologies that we employ include the use of gain of function and loss of function assays involving misexpression of cDNAs, RNA interference with siRNAs and shRNAs, lentiviral-mediated gene transfer and silencing, transgenic and conditional bigenic mice and morpholino-modified antisense-oligonucleotides.The systems we use include frog, chick and mouse embryos, mouse transgenesis, viral vectors, transducing proteins and culture of mouse and human cell lines, primary cells and stem cells.
2- Disease: Our research on the pattern formation of early embryos has taken us to study two types of diseases. i- diseases due to cell loss, such as Parkinson’s disease, and ii- diseases due to non-homeostatic increase in cell number, such as cancer. i- Work on stem cells and precursors in the brain suggests that one may be able to use the Sonic hedgehog-Gli pathway to stimulate proliferation/replenishment of cells that give rise to neurons derived from responsive precursors. In this area we study the role and potential of Gli proteins to specify dopaminergic cell fate and to expand appropriate stem cell populations. ii- Our focus on cancer stems from our initial work on the induction of epidermal tumors by misexpression of GLI1 and the proposal that all human sporadic basal cell carcinomas derive from the inappropriate activation/maintenance of the Hedgehog-GLI pathway.We presently work on role of this signaling pathway in skin, brain, prostate and breast cancers both to understand how its deregulation leads to tumor initiation and to understand how it is required for tumor maintenance.Following our work showing for the first time that sustained HH-GLI signaling is required for tumor growth and survival, we continue to investigate the participation of GLI proteins in sporadic human tumors, with the goal of developing a rational, wide-spectrum anti-cancer therapy.