We study, during cell determination the control of gene expression induced by modifications of the intracellular calcium concentration. Dysfunction of calcium signalling pathways can modify the phenotype of a given cell. Some severe genetic diseases which affect proliferation and/or cellular differentiation have for origin mutations occurring on elements involved in [Ca2+]i regulation. We want to understand how a [Ca2+]i increase can activate a suitable transcriptional pathway during early developmental phases. Our work investigates two aspects during early development in vertebrates.
Our biological models are the amphibian Xenopus laevis and the mouse.
We have demonstrated that neural induction is an instructive process where [Ca2+]i increase triggered by the activation of L-type calcium channels plays a is necessary and sufficient role to turn the fate of ectodermal cells from epidermis toward neural tissue. This work, led us to study more precisely, how calcium controls gene expression during neural induction (see figure) .
Through the construction of a Ca2+-dependant subtractive library we have isolated an arginine N-methyl transferase, xPRMT1b. The expression of this gene is induced directly by Ca2+. xPRMT1b plays a key role during neural determination by controlling the expression of the early proneural gene Zic3 (see articles n° 2, 5, 7, 9, 12, 17, 21)..
Our work evolved toward the characterisation of factors which can stabilize the neural fate in order to engage the ectoderm cells in the neuronal pathway differentiation (see article n°3)
We wonder how Ca2+ signalling controls the determination of intermediate mesoderm cells towards pronephric fate and how it controls the formation of kidney tubules. Ca2+ transients are observed in the pronephric territory, throughout gastrulation and these Ca2+ transients are necessary signals for pronephric tubule formation. (see articles n°1, 6, 11, 22)
A collaboration established these last years, with immunologists, have confirmed the importance of calcium signalling pathways in the control of differentiation of TH2 lymphocytes (see articles n° 4, 13, 19).
Since 1997 we organize annually in relation with CNRS (formation permanente Midi-Pyrénées) a theoretical and practical workshop on calcium signalling. The topics are renewed each year. The courses since 1999 can be obtain on this link.
GDR n°2688 We have done with CNRS a GDR (Groupement De Recherche). The main goal is to structure in France, an interdisciplinary research in order to understand the role of calcium in gene expression in normal and pathological situations. The GDR 2688includes 20 french teams and brings together researchers from plant and animal communities through meetings, participation in seminars and other workshops. (director M. Moreau)
The GDR 2688 has given the foundations to build a network gathering the best European experts in the calcium signalling field. Drug discovery and development are based on the paradigm “one gene, one protein, one function, one pathology”. The stagnation in new drugs development, despite a near-exponential increase in investment, is due to limitations of this paradigm. It is important to explore other concepts and in particular to seek for molecules active on signalling networks rather than on identified targets. To be able to quantitatively model the calcium signalling pathway in a given cell type and in a specific physiological state remains a challenge which, will be the cornerstone in the search for drugs acting on a regulatory pathway. By gathering and structuring the knowledge of the best European experts in the calcium signalling field, we aim to establish this in silico approach that would open a new era in drug discovery. 10 European labs are concerned by this European GDR. (Responsible M. Moreau)
LIA “ROCADE” (ROle of CAlcium in cellular DEtermination)
Our team in Centre de Biologie du Développement has recently formed an LIA (CNRS joined international laboratory) with the team of Andrew Miller at Hong University of Science and Technology (HKUST). It is the first LIA created by CNRS with Hong Kong. UPS is a partner of this association. This LIA is the result of an active collaboration which started in 1988 between our two teams. The collaboration with Andrew Miller started and was supported since the beginning by CNRS and Foreign Affairs Ministry (EGIDE). These two labs have a complementary approach in developmental biology using Xenopus and Zebrafish as biological models. This LIA works toward several ends. It allows, using several complementary biological models to study calcium-dependent genes involved in early development. The LIA also stimulates the development on both sides of new cellular dynamic imaging techniques using luminescent probes and photon counting. This collaboration involves for each team of the LIA reciprocal and frequent stays of several weeks per year between Hong Kong and Toulouse, joint publications and in both direction exchanges of students and post doctoral researchers. (Directors M. Moreau in Toulouse and A. Miller in Hong Kong)
PUBLICATIONS 1. GILBERT T, LECLERC C, &MOREAU M (2011) Calcium: a multifaceted key player for renal organogenesis Biochimie (in press) 2. LECLERC C, NÉANT I & MOREAU M (2011) Early neural development in vertebrates is also a matter of calcium. Biochimie (in press) 3. NEANT I, DEISIG N, SCERBO P, LECLERC C & MOREAU M (2011) Xp54nrb a RNA-binding protein isolated from a Ca2+-dependent screen is expressed in neural structures during Xenopus laevis development. Int. J. Dev.Biol (...)