CDS Thesis Seminar: Interpretation and Scaling of Positional Information during Development

Marcos Nahmad

Cells in a developing animal require information about their relative position in order to function and differentiate appropriately. Recent studies have challenged the classical view that morphogen gradients, chemical signals that provide positional information during development, are interpreted in a concentration-dependent manner and have raised doubts about the mechanisms by which positional signals are translated into spatial patterns of gene expression. Here we combine theoretical tools and experimental work in Drosophila melanogaster to investigate the role of morphogen gradient dynamics in the interpretation of positional information and the ability of embryos to spatially scale their pattern distribution to changes in the size of the field.

First, we study how a gradient of the signaling molecule Hedgehog is interpreted to establish multiple patterns of gene expression along the anterior-posterior axis of the Drosophila wing disc. Using mathematical modeling as a hypotheses-generating tool, we predicted that positional information cannot be explained by different concentration thresholds from a static Hedgehog gradient. Instead, we propose that cells take into account their history of Hedgehog signaling exposure to determine patterns of gene expression. We provide experimental evidence that supports our model and conclude that gradient dynamics, resulting from the gene network architecture of the Hedgehog signaling pathway, determine pattern formation in the wing disc.

Second, we introduce a theoretical formalism to study the role of morphogen gradient dynamics in developmental patterning. Given a mathematical model of patterning in a system we define and compute parameter perturbations that maintain the steady-state morphogen signal invariant. We propose that this approach could be used as a tool to design genetic experiments to study the role of morphogen gradient dynamics.

Lastly, we use dorsal-ventral patterning of the early Drosophila embryo as a model to study scaling of gene expression patterns with respect to natural variations in axis length, this is, the ability to establish positional information relative to the size of the system. We provide evidence that gene expression patterns that depend on the maternal factor Dorsal, scale with the length of the dorsal-ventral axis. Furthermore, our data suggest that scaling in this system is a gene-dependent rather than a position-dependent property. We propose that the mechanisms for scaling depend on feedback interactions downstream of Dorsal.