Nuclear Pore Complexes (NPCs) are elaborate structures embedded in the nuclear envelope and composed of multiple copies of about 30 different proteins termed nucleoporins (Nups). Our team aims at characterizing, beyond their well-established function in transport between the cytoplasm and the nucleus, non-conventional functions of nucleoporins, notably in cell differentiation during development, chromatin organization, and mitosis.
Our previous work contributed to the characterization of a major structural sub-complex of NPCs, the Nup107-160 complex (also called “Y-complex“), and to highlight its role in NPC assembly, its contribution to various stages of mitotic progression, and its involvement in embryonic stem cell differentiation.
We are currently pursuing the study of the functions, regulation and direct partners of these nucleoporins in these “unconventional” activities. To do so, we use imaging, biochemical and genetic approaches (CRISPR/Cas9 strategies), in model systems such as human cell lines, but also in pluripotent stem cells (mESCs and hiPSCs) and their differentiated derivatives, including organoids. We are also pursuing studies in to understand the impact of nuclear pore basket proteins on chromatin organization and gene regulation during development.
By elucidating the normal role of these nucleoporins, our work should contribute to understanding the mechanisms by which mutations or misregulation of these nucleoporins lead to various pathologies (including renal pathologies, neurodevelopmental disorders, and cancer).
Figure 1: Nuclear pore complexes in mouse embryonic stem cells.
Left: Schematic representation of a nuclear pore and our proteins of interest (Y-complex, Tpr, and Mad1). Middle: Localization of a GFP-tagged nucleoporin (Seh1, one of the components of the “Y-complex”) to nuclear pores in interphase and to kinetochores in mitosis. Right: cell morphology after 7 days of neuronal differentiation. Note their self-organization in “rosette” structures.
Current research topics:
– Nuclear pore assembly
– Nucleoporins in genome organization and gene regulation.
– Nucleoporins in renal and neurodevelopmental pathologies
– Nucleoporins, kinetochores, and the cell cycle
Models: pluripotent stem cells (mESCs and hiPSCs), organoids, primary and cancer cell lines, oncogene-induced senescence, Drosophila.
Methods: genome editing, cell differentiation, cell imaging, transcriptomics, biochemistry, yeast-two-hybrid
Keywords: nuclear pores, nuclear envelope, chromatin, differentiation, cell cycle
Ongoing collaborations :
Corinne Antignac, Institut Image, Paris, France;
Brian Burke, IMB, A*Star, Singapore;
Andreas SCHEDL, Institut de Biologie Valrose, Nice, France;
Former collaborations :
Johannes LOFFING and Stephan C. F. NEUHAUSS, University of Zurich, Switzerland;
Bernardo REINA−SAN−MARTIN, IGBMC, Illkirch, France;
Elizabeth LACY, Memorial Sloan Kettering Cancer Center, New York, USA;
Raphael GUEROIS, Institut de Biologie et de Technologies de Saclay (iBiTec-S), Gif-sur-Yvette, France;
Richard VALLEE – Department of Pathology and Cell Biology, Columbia University, New York, USA;
Julien DUMONT, Institut Jacques-Monod IJM, Paris, France;
Lionel PINTARD, Institut Jacques-Monod IJM, Paris, France
GRANTS – FOUNDING
The team has been recognized as “équipe FRM 2020 ” by the Fondation pour la Recherche Médicale and was supported in 2019 by a grant form IDEX Université de Paris. The team has been supported by the Labex “Who am I?”, and currently hosts in its lab-space the members of the enSCORE facility, founded by the Labex “Who am I?”and dedicated to the development of neuronal organoids