Regulation of Cell-Fate Specification in the Mouse
Themes and areas of research : Quantitative biology and modeling , Development and evolution , Cellular dynamics and signaling , Genome and chromosome dynamics , Models , Molecular and cellular pathologies
We are studying the molecular basis of lineage specification in the early mammalian conceptus. It has been shown in the mouse, the animal model of choice, that all major signalling pathways are involved. These pathways also participate in the maintenance and the renewal of tissues later in life, functions that place them at the centre of many pathological situations. The study of their implication and interplay during early developmental events, when the organism is still relatively simple, is therefore particularly relevant to our understanding of their functions in later, more complex, contexts.
We focus on NODAL, a signalling molecule that plays important roles during development. NODAL is a TGFß family member signalling via the SMAD2/3 pathway, also known as the ACTIVIN/NODAL signalling pathway. The Nodal gene is required for the establishment of embryonic axes. It is also required for the specification and maintenance of various cell identities, both in embryonic and extra-embryonic lineages. Several of these cell types are motile. Over the years the Nodal locus has been extensively studied, its enhancers identified and characterized, and it has become a valuable model to study how various regulatory inputs (TGFß, WNT and NOTCH signalling, pluripotency factors, etc…) are integrated to ensure that a certain gene is expressed in a certain cell at a certain time.
While a lot is known about the role of NODAL during early development, its role in the adult has not been extensively studied, although its expression has been detected in a number of tissues. It is notably expressed in tissues that undergo periodical renewal or remodelling under the control of hormonal stimuli, such as the endometrium and the mammary gland. In human, the expression of NODAL has been detected in tumour cells from different cancer types, and it has been associated with their plasticity and invasive behaviour, suggesting its role there may reflect its functions in embryonic and adult tissues.
We are currently using a combination of genetic, biochemical and imaging approaches to investigate NODAL function during the establishment and maturation of early embryonic lineages, using both the mouse embryo and in vitro culture models relying on the use of embryonic stem cells. We also use the same approaches in human melanoma cell lines to investigate the function and regulation of NODAL during tumour progression. We have established important collaborations with biophysicists, providing us with access to valuable expertise in microfabrication, microfluidics, image analysis, the use of adhesive micropatterns and omic data analysis.
Embryo patterning, regulation of gene expression, differentiation, mouse embryo, pluripotent stem cells, melanoma cell lines, TGFß signalling, pluripotency factors, chromatin.
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Souilhol C*, Perea-Gomez A*, Camus A, Beck-Cormier S, Vandormael-Pournin S, Escande M, Collignon J and Cohen-Tannoudji M. (2015). Notch activation interferes with cell fate specification in the gastrulating mouse embryo. Development 142, 3649-3660.
Cajal M, Creuzet S, Papanayotou C, Sabéran-Djoneidi D, Chuva de Sousa Lopes SM, Zwijsen A, Collignon J and Camus A. (2014). A conserved role for non-neural ectoderm cells in early neural development. Development 141, 1-12.
Papanayotou C and Collignon J. (2014). Activin/Nodal signalling before implantation: setting the stage for embryo patterning. Phil. Trans. R. Soc. B 369: 20130539.
Papanayotou C, Benhaddou A, Camus A, Perea-Gomez A, Jouneau A, Mezger V, Langa F, Ott S, Sabéran-Djoneidi D, Collignon J. (2014). A novel Nodal enhancer dependent on pluripotency factors and Smad2/3 signaling conditions a regulatory switch during epiblast maturation. PLoS Biol 12(6): e1001890.
Mazari E, Zhao X, Migeotte I, Collignon J, Gosse C, Perea-Gomez A. (2014). A microdevice to locally electroporate embryos with high efficiency and reduced cell damage. Development 141, 2349-59.
Cajal M, Lawson KA, Hill B, Moreau A, Rao J, Ross A, Collignon J, Camus A. (2012). Clonal and molecular analysis of the prospective anterior neural boundary in the mouse embryo. Development 139, 423-36.
Granier C*, Gurchenkov V*, Perea-Gomez A, Camus A, Ott S, Papanayotou C, Iranzo J, Moreau A, Reid J, Koentges G, Sabéran-Djoneidi D, Collignon J. (2011). Nodal cis-regulatory elements reveal epiblast and primitive endoderm heterogeneity in the peri-implantation mouse embryo. Dev Biol 349, 350-62.