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Paracrine and transcriptional control of embryogenesis

Research project P6/20 (Research action P6)

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Description :

Developmental biology aims at identifying and understanding the complex and highly connected regulatory pathways that make embryonic cells change their fate and differentiate, that pattern the embryo, and that establish its organ systems. It integrates multiple disciplines, including molecular biology, genetics, cell biology, signal transduction, and regulation of gene expression. The complexity of the field, and the practically obligatory use of more than one model organism, led us five years ago to create an IAP network that brought together several Belgian teams actively involved in the area of developmental biology (IAP 5th phase, project 35, referred to as IAP-V). The performance of this network, entitled “Paracrine and transcriptional control of early and late embryogenesis in vertebrates” was considered as ‘excellent’, both in terms of scientific quality and partnership, during the ex-post evaluation. In particular, the partners shared expertise in regulatory molecules and signaling pathways in specific tissues/organs, and the consortium provided a unique opportunity to tackle complementary scientific questions using different animal models such as mouse, Xenopus and zebrafish.

Therefore, for the 6th phase, we propose to extend and expand this successful multi-disciplinary project. Whereas Dr. L Leyns withdraws from the consortium, we have now included three novel, worldwide renowned partners in the field of developmental biology: C.L. Mummery (foreign partner), A. Goffinet and L. Moons. As such, the strategic importance of this network remains unchanged: it aims at bundling, consolidating and expanding expertise in modern developmental biology in Belgium, based on the successful projects in IAP-V. Hence, it continues to represent a concerted effort to acquire the critical intellectual and technological mass, and flexibility, required for rapidly and effectively addressing key questions in developmental contexts, often with direct relevance to medicine. Despite the inevitable heterogeneity between the different groups, the proposal reflects a genuine effort at integration rather than just adding skills, expertise, topics, molecules and tissues to each other. It does so by regrouping investigators with common interests, but complementing expertise in specific signaling pathways, developmental processes, experimental approaches and model organisms. With B. Hassan and P. Zimmermann, who are joining efforts with the group of G. David, the network will now also have access to the Drosophila model and to live imaging technology, as suggested by the ex-post evaluators.

The major objectives of the new research program of this network are:

1) To study the mechanisms involved in the development of selected tissues and organs. We unified the projects in the different research groups in a program that will focus on the formation and patterning of the three germ layers during gastrulation and on the development of the cardiovascular system, the nervous system (CNS and PNS), and endoderm derivatives (liver and pancreas).

2) To investigate the role of selected transcription factors (zinc finger and helix-loop-helix factors), signaling pathways (TGFb, Notch, Eph/ephrin, VEGF) and modulators thereof (like proteoglycans, scaffolding proteins, non-coding RNAs) in the development of these tissues and organs.

3) To unravel different functions for selected proteins dependent on the cellular context. The parallel investigation of the same proteins in different processes/tissues (i.e. VEGF, netrins, reelin and ephrins in axonal and vascular guidance; Smad5 and endoglin in heart and vasculature; HNF6 in liver and pancreas; MyT1 and IA1 in neural and pancreas development etc) favors distilling common themes or dissimilar functions/features of proteins or processes; the emerging strong mechanistic similarities of neuronal and vascular (co)development and the role of VEGF, netrin and ephrins therein being a typical example.

4) To ensure access for each participant, through project-based collaborations and/or training of young researchers, to several animal model systems, i.e. zebrafish, frog (Xenopus), mouse and Drosophila, each providing specific experimental advantages, and to mouse and human embryonic stem (ES) cell systems.

5) To consolidate the interactions between the different partners (exchange and transfer of technology and know-how, training, meetings), which have complementary expertise, and to reinforce in Belgium a center of excellence for Developmental Biology. Furthermore, we anticipate this networking will also constitute the driving force for an appealing PhD-training program in Developmental Biology. Such a program, and the interactions with our European partner (C.L. Mummery, NIOB, Hubrecht Laboratory, the Netherlands), will further enhance the international exposure of the Belgian Developmental Biology community and may attract brilliant young scientists to Belgium.

As in the previous IAP project, the new network will keep the matrix organization for its work packages (WP); this was recognized by the evaluators as a key element for success by triggering new collaborations or innovative approaches. The present project is built around 7 workpackages (WPs) focusing either on the roles of particular transcription factors, signaling pathways and their modulators in embryogenesis (WP1 to WP3) or on the development of selected organs and tissues (WPa to WPd). Each partner of the present network has a special expertise and interest in at least one of the WPs. These work packages are:

“ Regulatory factors oriented WPs ”

WP1 : Transcription factors

• Zinc finger factors
• Helix-Loop-Helix factors

WP2 : Signaling pathways

• TGFb pathway
• Ephrins and Eph receptors
• VEGF family
• Delta-Notch pathway

WP3 : Modulators

• Proteoglycans
• Intracellular PDZ scaffold proteins
• Non-coding RNA

“ Tissue oriented WPs ”

WPa : Early developmental decisions
WPb : Development of the vascular system
WPc : Development of the nervous system
WPd : Development of the endodermal derivatives

We anticipate – like in the previous IAP-V project - several major areas of interaction, at both the thematic and technical levels. The access to different model organisms and ES cell systems, the overlapping interests and the combination of complementary expertise of the various partners within this network will tremendously accelerate the pace of progress and discovery of mechanisms of action of complex and highly connected regulatory pathways determining different developmental processes.

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