Matias SimonsEpithelial biology and disease, Institut Imagine - Inserm / Université Paris-Descartes
Mes recherches
My research combines basic biology with disease mechanisms and has from the beginning been strongly influenced by human genetics. After my MD thesis on glomerular slit diaphragms, I worked as a clinical resident and postdoc with Gerd Walz (University Hospital Freiburg), focussing on inversin, a ciliary protein that when mutated gives rise to cystic kidney disease in humans. I discovered that the primary cilium can control the balance between two branches of the Wnt pathway, the canonical and the non-canonical Wnt or planar cell polarity (PCP) pathway, suggesting that cyst formation may be caused by misoriented cell division or cell migration. Intrigued by the PCP pathway, I decided to do a joint postdoc in the Drosophila labs of Michael Boutros and Marek Mlodzik at the German Cancer Center (Heidelberg) and Mount Sinai (New York), respectively, where I performed a cell-based genome-wide RNAi screen to identify new regulators of PCP signaling. Returning to Germany in 2009 to set up my own independent lab as an Emmy-Noether fellow by the German Research Foundation (DFG), I focussed on one of the screen hits, the V-ATPase subunit ATP6AP2. At Institut Imagine, where I have been a group leader and Liliane Bettencourt Chair for Developmental Biology since 2014, I have continued this line of research (see ATIP-Avenir project). Moreover, I combine Drosophila, cell culture and mice as functional validation tools in human genetics, notably for genetic diseases of renal proximal tubules.
Mon projet ATIP-Avenir
Cellular programs for lysosomal stress: lessons from ATP6AP2 inactivation
Lysosomes have recently emerged as control centers for cellular homeostasis. The diverse consequences of lysosomal dysfunction are illustrated by the inactivation of the lysosomal transmembrane protein ATP6AP2 in Drosophila. Here, lack of ATP6AP2 leads to cell-autonomous effects such as reduced organellar acidification and protein degradation as well as to a severe impairment of tissue growth and polarity. We could recently show that the majority of these phenotypes are due to the disturbance of a lysosomal complex consisting of the proton pump V-ATPase and mTOR components. Using our fly model, we could also demonstrate that proteinuric kidney diseases can be caused by impaired signaling from this lysosomal complex.
We now wish to gain further knowledge on the cellular programs that are triggered upon lysosomal dysfunction. For this, we will use a combined transcriptomics and RNAi screening approach for suppressors of the ATP6AP2 growth phenotype in Drosophila. The aim is to identify effectors and target genes for mTOR-controlled tissue growth and endocytosis. In a complimentary work package, we will study the role of ATP6AP2 in the development and maintenance of a complex organ like the mammalian kidney. This will be achieved by the nephron-specific inactivation of murine ATP6AP2 using an inducible and conditional allele. Finally, we will use a candidate gene approach for the identification of novel mutations in human individuals with Dent’s disease, a proteinuric kidney disease with defective endocytosis in the proximal tubules.
With our integrated work program we expect to generate important insights into the cellular consequences triggered by lysosomal stress. We hope that this may lead to the improvement of therapeutic options in Dent’s disease and lysosomal storage disease, in general.