Blanc SVSE 2 - Sciences de la vie, de la santé et des écosystèmes : Biologie cellulaire, développement

The architecture of elongation, a basic developmental process – DEV-PROCESS

How the development of the embryo organizes the genome and how the organization of the genome facilitates the evolution of development.

The goal is to determine the basic cellular processes that together constitute a developmental process, which of these operations have the properties of genetic modules and if certain combinations of modules are co-controlled by the same genes.

The challenge is to provide an example of an analysis that at long term will prove the organization of the genome through its functioning during development.

The project starts from the trivial remark that genomes are not just combination of genes and of intergenic sequences but elements of systems. Other components of these systems are the genes products and the external factors. This conclusion was first reach more than fifty years ago with bacteria. It seems that the development of multicellular organisms is fully reducible to this equation. It is the demonstration of this hypothesis that constitutes the major challenge of the program. However, with development systems are extraordinarily dynamic and the external factors include those of multicellular organisms. It follows that for a given cell they include their neighbours and the intercellular space. In addition, these systems control genes, which together confer to the cells their properties (motility, shape, asymmetry etc). It is these different levels of integration and interaction of the elements in these systems that now need to be discovered.

The knowledge of the behaviour of cells makes possible to determine what cellular processes are involved in a given developmental process. Clonal analysis using RCA helps reconstructing many stages of the morphogenesis of a structure since RCA clones are randomly produced in both time and space. Clonal analysis using GICL zooms on a particular step and allows generating unlimited number of clones whose date of birth is known. When ubiquitous, GICL produces random clones in relation with the three spatial dimensions. RCA and GICL are two complementary approaches that allow determining where and when 4D imaging should be undertaken. Recent progress of confocal microscopy and live imaging help understanding the dynamic aspect of cell behaviour (migration, division, shape and size changes). It is the groupings of the cellular processes involved in a developmental process that needs to be identified. The use of various animal models chosen for their evolutionary position at key positions of evolution, amphioxus, zebrafish and mouse is instrumental to determine the variety of combinations of operations corresponding to a given developmental process.

Since the beginning of the project, we have delivered two papers, a scientific article: «Redefining the structure of the hair follicle by 3D Clonal analysis,« Sequeira, I and Nicolas, JF, Development. 2012, in press, and a review article: «Hair Follicle Stem Cells,« Legue E., Sequeira I., and J.-F. Nicolas, in «Stem cells and cancer stem cells«, Hayat, MA ed. , 2012. Volume 3: 35-47. In the scientific article, we redefine the structure of the mouse HF using clonal analysis. We found a new lineage whose role must now be determined. We clarified the origin of the elements of the HF outer layer and we elucidated the growth patterns of all anagen HF structures. A third publication is being finalized. It will report the development of a ubiquitous GICL system for the mouse embryo, exclusive of spontaneous background labelling until at least E14.5. In the zebrafish and amphioxus, we have developed new strategies that pave the way for the investigation of cell behaviour in their embryo. We have demonstrated the feasibility of GICL in zebrafish allowing comprehensive description of lineages and growth patterns in fish. Our preliminary results from 4D imaging in amphioxus suggests that elongation could be summed up in only one component, the orientation of mitoses, which is different from the composite elongation in vertebrates.

The central idea of this project that developmental processes organized genomes and that in turn genome organization accelerates the evolution of development has many implications. It leads naturally to the concept of the organization of the molecules of live (intergenic DNA, genes and their products) in dynamic systems. It follows a new vision of living phenomena, which moves away from the purely molecular view still very prevalent in the public (a gene a process, a gene a disease etc). Indeed, the organization of molecules in systems whose elements interact, help understanding the level of interdependence of the elements of any normal or pathological biological processes. As these processes occur in the system that the genome, its products and the elements constitute, knowledge of genome organization is crucial. The fact that the very detailed study of the development is absolutely necessary to reveal the organization of genomes is perhaps not so natural. Our results provide specific examples on this point and therefore participate in this enormous change of perspective.

Redefining the structure of the hair follicle by 3D Clonal analysis », Sequeira, I and Nicolas, J.F, Development, 2012, sous presse.
Hair Follicle Stem Cells », Legué E., Sequeira I., and Nicolas J.-F., Stem cells and cancer stem cells, Hayat, M.A. ed. 2012. Volume 3: 35-47.
Rubio-Guivernau JL, Gurchenkov V, Luengo-Oroz MA, Duloquin L, Bourgine P, Santos A, Peyrieras N, Ledesma-Carbayo MJ. Wavelet-based image fusion in multi-view three-dimensional microscopy. Bioinformatics. 2012 Jan 15;28(2):238-45. Epub 2011 Nov 9.

The project intends to define at the cellular level, the architecture (design) of a basic developmental process, the elongation. We will characterise its elements and try to define their arrangement in operational modules. The proposed methodology to reach this goal consists of comparing the elongation of the embryo of several species (during gastrulation and tail bud stages) and also of different structures within the same species. These phylogenetic and ontogenetic comparisons of the same process should in turn reveal organisational principles, maybe shared with other developmental processes underlying formation of the body plan and of specific body structures. In particular, it should allow understanding their coupling with genetic patterning (the assignation of regulatory states to cells). The elongation of the embryo of three chordates, mouse, zebrafish and amphioxus and the elongation of a structure formed during organogenesis, the hair follicle (HF), will be studied.
From our current understanding of the elongation process, it becomes apparent that elongation relies on the combination of basic cell operations. Specificity of this process in different contexts seems to depend on the multiplicity and specific arrangement of these basic operations as exemplified by the comparison of elongation in structures with increasing complexity (renal tubule, HF, axis). In the context of the embryo, it is clear that multiple operations are involved in different tissues and these need to be coordinated within and between tissues. The project proposes systematic large-scale clonal analysis and 4D imaging/cell tracking to reveal the series of operations involved in the elongation of three representative chordate embryos and the HF. This will allow through phylogenetic and ontogenetic comparisons of the operations involved to define the elementary cell behaviours and their arrangement underlying the elongation process.
The project is based on two assumptions: (1) the development of a species is a variation of the development of a more basal species. Thus, a major constraint in the organisation of a developmental operation is its previous structure (2) developmental variations concern mainly the relationships of cells or groups of cells in time and space. This assumption is supported by the role of intercellular signalling in development, as indicated by genetic analysis. As a consequence, to understand a developmental process, it seems appropriate to compare this process in several species, chosen on the basis of their phylogenetic position, and also in different structures of a single species to reveal its ontogenetic plasticity. The study of cell dynamics and behaviour (growth mode, cell rearrangement, shape and size of the embryonic territories etc.) is essential as these factors impact the relationships between cells and between territories
These considerations guide the strategy of this application: (1) the study of several chordates: the mouse, our goal being to understand a development close to that of humans; the amphioxus, a cephalochordate still close to the most ancestor group of the chordate phylum and the zebrafish, an intermediate between amphioxus and mouse. (2) the study of a structure produced during organogenesis, the HF, opening the route of comparative ontogenetic analysis.
Our goal is to define the elements involved in the process of elongation and to find how they are arranged to form an integrated operation. Elongation is used by the embryo of the three species to extend their body and by the HF during its growth phase, but apparently with different modalities. These differences will help defining the basic elements. The approach has similarities with the analysis of the interactions within transcription networks and between different transcription networks type that allow defining network motifs to which elementary functions can be associated.

Project coordination


The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.



Help of the ANR 405,704 euros
Beginning and duration of the scientific project: - 36 Months

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