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Coordination Of Patterning And Growth In The Spinal Cord

Periodic Reporting for period 3 - GROWTHPATTERN (Coordination Of Patterning And Growth In The Spinal Cord)

Reporting period: 2019-07-01 to 2020-12-31

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 morphogen signaling gradients, the rate of tissue growth and the gene expression pattern. 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.
Throughout the reporting period we have begun working on the three main aims:
1) How do opposing morphogen gradients specify pattern?
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.
2) How do morphogens control neural tube growth?
We used a novel lineage tracing approach to accurately measure the growth rate and growth anisotropy within the neuroepithelium at different developmental stages. We also developed an in silico (vertex) model of the neuroepithelium which allowed us to uncover a relationship between the growth rate and growth anisotropy of the tissue. These methodological advances will allow us to accurately measure how tissue growth is altered by perturbations in morphogen signaling.
3) What are the feedbacks between growth of the morphogen source, morphogen gradient shape and pattern.
We have established an approach with which to accurately measure and perturb the growth of the morphogen source. In the process of establishing this approach, we have uncovered novel properties of the morphogen source that we are currently investigating further.
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 also made progress on Aims 2 and 3 of the project. In particular, we have established a data-driven computational cell based model of the neural tube epithelium, which will be instrumental in understanding the feedbacks between tissue growth and morphogen signaling. To do this, we employed a state-of the art lineage tracing approach that has not been previously used in this tissue. Moreover, we have obtained experimental results from live imaging experiments on the growth dynamics of the Shh source and are using this as a basis to develop a computational model of this tissue. We expect that the results of these ongoing projects will allow us to gain new insight into the feedbacks between morphogens and tissue growth in spinal cord development.
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