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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - GROWTHPATTERN (Coordination Of Patterning And Growth In The Spinal Cord)

Teaser

Summary

Individuals of the same species can differ widely in size, but the structure and function of their organs is highly reproducible. To understand how this reproducibility is achieved, we are interested in the basic mechanisms that control the growth and gene expression pattern in the organ, which later defines its structure. During embryonic development, molecules, called morphogens, control both growth and pattern. Morphogens are secreted by cells in specialized locations and form gradients of concentration across the organ.

Our goal is to determine the relationship between the concentrations of different morphogens and their effect on the frequency with which cells divide and the gene expression. To approach this, we develop experiments that allow precise manipulation and measurements of morphogen activity and cell divisions. In addition, we study how growth itself may affect morphogen activity and pattern. We use the mouse and chick spinal cord as a model system, but the principles are likely to apply to many organs and in vitro engineered tissues. The basic understanding of how morphogens work to control growth and pattern will help understand disease states such as cancer and embryo malformations.

Work performed

Throughout the reporting period we have begun working on the three main aims:
1) How do opposing morphogen gradients specify pattern?
2) How do morphogens control neural tube growth?
3) What are the feedbacks between growth of the morphogen souce, morphogen gradient shape and pattern. The major emphasis of our work so far has been on the first aim. Here we uncovered a novel mechanism by which cells integrate information from the opposing BMP and Shh gradients that allows for the establishment of precise tissue pattern. This optimal decoding strategy is implemented in cells using a morphogen-driven transcriptional network. This mechanisms explains how pattern is accurately established and further maintained at late developmental stages, when the morphogen signaling levels decrease. These results lead to a publication in the journal Science in 2017.

Final results

Our findings on the interpretation of the opposing morphogen gradients of Shh and BMP is the first demonstration of such a mechanism in a growing tissue. Previously, decoding of opposing gradients has been quantitatively studied in the context of the non-growing syncytium of the Drosophila blastoderm, however, addressing this issue during vertebrate organ growth has remained a challenge. Our quantitative approach combining in vivo genetics, ex vivo quantitative assays using chick explants and mathematical modeling have provided us with an unique opportunity to study the interpretation of opposing morphogen gradients with unprecedented spatio-temporal resolution. This represents a major advance compared to the state of knowledge at the beginning of the reporting period.
We have recently begun to focus our effort on Aims 2 and 3 of the project and investigate the role of morphogens in regulating tissue growth, as well as the effects of growth on morphogen gradient formation and pattern. We are making progress on analyzing the effects of Shh and BMP signaling on progenitor cell survival and proliferation, in vivo, as well as in ex vivo assays. At the same time, we are investing effort in establishing live imaging of mouse embryos and lineage tracing analysis of the growth patterns during early neural tube development. We expect that these efforts will generate novel data and are planning to analyse it in the context of theoretical frameworks to gain new insight into the feedbacks between morphogens and tissue growth in spinal cord development.