Cell Cycle and Development
- Lionel PINTARD
Tel.: +33 (0)157278089
Contact par email
Our group is interested in the molecular mechanisms that control the cell cycle machinery during development.
Control of the cell cycle is a fundamental aspect of cell biology. Such control is essential for the normal development of an organism, which requires a precise orchestration of cell proliferation, cell differentiation and morphogenesis. Breakdown of cell cycle control has drastic consequences and leads to cell death, genome instability or deregulated growth, typical of cancer.
Despite considerable advances in our understanding of the mechanisms of cell cycle progression in single cells, much less is known about the coordination of the cell cycle and development in a multicellular context. For example, in the early C. elegans embryo, asymmetric cell divisions produce descendants whose cell cycle durations are different (Figure 1). This asynchrony appears essential for proper cell fate determination and normal development. Nevertheless, how this asynchrony is established and maintained during embryogenesis is poorly understood; the nature of the signaling events and targeted cell cycle components is still largely unknown.
Figure 1: One-cell C. elegans embryos in mitosis (upper panel) stained with anti-tubulin antibodies (green) and co-stained with a DNA dye (bleu). The division of the one–cell embryo is asymmetric and gives rise to 2 blastomeres (AB and P1) of different sizes (middle panel), which divide asynchronously (lower panel). Chromosomes were visualized by GFP-tagged histone H2B (green). Dimension of the embryo: 55 (µm in width) X 30 (µm in height).
Our goal is to shed light on the molecular mechanisms governing cell cycle division during animal development. We are using as a model system the nematode C. elegans, since this organism provides a powerful setting in which cell cycle control can be genetically analyzed during development by combining cell biology techniques and proteomics. More specifically, we are investigating the role and regulation of Cullin-RING ubiquitin-ligases (CRLs) during C. elegans development. CRLs are the largest family of ubiquitin-ligases, and its members selectively target diverse protein substrates such as cell cycle regulators for ubiquitin-dependent degradation by the 26S proteasome (Figure 2). Although the molecular composition of CRLs is beginning to emerge (Figure 3), only a small subset of substrates has as yet been identified.
We are focusing our research on the following questions:
- What are the functions of CRLs during C. elegans development' What are their critical substrates and the function of these substrates'
- How are CRLs regulated'
- What is the molecular basis for distinct cell cycle duration in the early C. elegans embryo?
These studies, in which we aim to identify the basic molecular mechanisms that control cell cycle division in the context of animal development, are critical to our understanding of both development and oncogenesis.
Figure 2: The Ubiquitin-proteasome System:
Substrate proteins are linked to ubiquitin through a series of trans-thioesterification reactions catalyzed by a enzymatic cascade (E1 E2 E3). Reiteration of the catalytic cycle assembles a polyubiquitination chain, which acts to target the substrate to the 26S proteasome.
Figure 3: Composition of Cullin-RING Ligases (CRL)
Work in our laboratory is supported by the CNRS, the Association pour la recherche sur le cancer , the Fondation pour la Recherche Médicale and the City of Paris.
This group is part of the Labex “Who am I?”
Selection of Publications
CRL2LRR-1 E3-Ligase Regulates Proliferation and Progression through Meiosis in the Caenorhabditis elegans Germline. Burger J, Merlet J, Tavernier N, Richaudeau B, Arnold A, Ciosk R, Bowerman B, Pintard L.
PLoS Genetics. 2013 Mar; 9(3):e1003375.
The CRL2LRR-1 ubiquitin ligase regulates cell cycle progression during C. elegans development. Merlet J, Burger J, Tavernier N, Richaudeau B, Gomes JE, Pintard L.
Development. 2010 Nov;137(22):3857-66.
Control of the oocyte-to-embryo transition by the ubiquitin-proteolytic system in mouse and C. elegans. Verlhac MH, Terret ME, Pintard L.
Curr Opin Cell Biol. 2010 Dec;22(6):758-63. Epub 2010 Oct 11. Review.
An interaction network of the mammalian COP9 signalosome identifies Dda1 as a core subunit of multiple Cul4-based E3 ligases. Olma MH, Roy M, Le Bihan T, Sumara I, Maerki S, Larsen B, Quadroni M, Peter M, Tyers M, Pintard L.
Journal of Cell Science 2009 Apr 1;122(Pt 7):1035-44.
Regulation of cullin-RING E3 ubiquitin-ligases by neddylation and dimerization. Merlet J, Burger J, Gomes JE, Pintard L.
Cell Mol Life Sci. 2009 Feb 6.
Dernière modification 23/04/2013