MORPHSIG · Precision and interpretation of signaling in embryonic development of the vertebrate nervous system
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2006-07-01 → 2008-06-30
- EU contribution
- €168,231
- Participants
- 1
- Scheme
- EIF
Lines connect the coordinator with its partners.
Results in brief
Final Activity Report Summary - MORPHSIG (Precision and interpretation of signalling in embryonic development of the vertebrate nervous system)
The transformation of naive cells in a developing tissue into an organised arrangement of cell differentiation is fundamental to the development of multicellular organisms. In many developing tissues graded signals - morphogens - act as positional cues to control the pattern of cell fate specification. The activity of a morphogen has generally been viewed as a concentration-dependent response to a diffusible signal, but the duration of morphogen signalling can also affect cellular responses. One such example is the morphogen Sonic Hedgehog (Shh). In the central nervous system and limbs, the pattern of cellular differentiation is controlled by both the amount and the time of Shh exposure. How these two parameters are interpreted at a cellular level has been unclear. Here we provide evidence that changing the concentration or duration of Shh has an equivalent effect on intracellular signalling. Cells convert different concentrations of Shh into time-limited periods of signal transduction, such that signal duration is proportional to Shh concentration. This depends on the gradual desensitisation of cells to ongoing Shh exposure, mediated by the Shh dependent upregulation of Ptc1, a ligand binding inhibitor of Shh signalling. Thus, in addition to its role in shaping the Shh gradient, Ptc1 participates cell autonomously in gradient sensing. Together, the data reveal a novel strategy for morphogen interpretation, in which the temporal adaptation of cells to a morphogen integrates the concentration and duration of a signal to control differential gene expression.
Data: CORDIS, © European Union
Project objective
Of great importance during embryonic development are secreted signaling molecules that control the differentiation, proliferation and patterning of forming tissues. Many of these signals act in a graded fashion to control cell behaviour in a concentration dependent manner. Sonic Hedgehog (Shh) is an example of such a signal that controls the generation of distinct neuronal subtypes in the neural tube. In response to Shh signalling, the ventral neural tube is divided into compartmentalised progenitor pools, e ach of which generates distinct neuronal progeny. The boundaries between adjacent progenitor pools are delimited by sharp, patent changes in gene expression and the remarkable precision of these boundaries, together with the absence of intermixing of cells from adjacent pools, represents a critical step in the interpretation of graded Shh signalling. Here we aim to determine the mechanisms involved in this poorly understood process. We will focus on the role of cell-cell contact and differential cell adhesion. To this end, we will develop novel in vitro and in vivo approaches that combine state-of-the-art live imaging techniques and the latest chick transgenic technology. These will allow me to assay this process and provide powerful functional tests for candidate molecules and analysis of the epistatic relationships between the different molecular partners. The project addresses questions that are at the forefront of research in developmental neurobiology, and more generally in biology. Knowledge of the mechanisms that confer precision to graded Shh signalling will advance our understanding of neural tube development and provide insight into general strategies that endow morphogen gradients with their extraordinary accuracy. Moreover, the basic science quest ions addressed in this project are of direct relevance to basic and therapeutically applicable stem cell research, in particular, the use of stem cells for analysing and treating neurodegenerative diseases.
Original text from CORDIS.
Participants
- MEDICAL RESEARCH COUNCIL · LONDONCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union