Dynamic regulatory mechanisms of robust pattern formation in the neural tube

Harvard Medical School, Boston MA

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Abstract

? DESCRIPTION (provided by applicant): The long-term goal of our research is to understand the principles that permit developmental systems to robustly construct embryos of the correct pattern, shape, and size. Developmental systems face a gamut of variations from different sources including environmental, genetic, and stochastic, which manifest at multiple levels from molecules to cells to organs. In the face of these challenges, organisms have been designed through evolution to buffer the phenotype against these variations in order to robustly achieve a developmental norm, a process Waddington termed canalization. As our knowledge of the molecular and cellular details of patterning systems has expanded, there is now the opportunity to understand the systems level mechanisms that give rise to robust pattern formation. Here we focus on dorsal-ventral patterning of the neural tube where it is thought that a smooth and steady gradient of the signaling molecule Sonic Hedgehog acts as a morphogen to precisely specify different domains of neural progenitors at defined positions as a function of concentration. Using a novel approach developed in my lab called in Toto imaging in zebrafish, we have discovered that in reality both the morphogen source and response are noisy and dynamically changing as cells make fate decisions. We have found that this noisy and dynamic morphogen results in specification of fate-restricted progenitors in a mixed and overlapping pattern. Directional sorting of specified cells then corrects these positional errors resulting in sharply defined domains. Remarkably, forced specification of motor neuron progenitors at ectopic locations causes these cells to move to the motor neuron progenitor (pMN) domain and replace the would be pMN cells resulting in a normally patterned and viable embryo formed from a very different developmental trajectory. Here we seek to elucidate the mechanisms underlying this robustness. Using a combination of quantitative time-lapse imaging, precise genetic perturbations, biophysical measurements, and modeling, we will: 1) Decode how a large diversity of temporally increasing Shh signals are processed to give rise to a small set of discrete cell fates; 2) Determine the mechanism of cell sorting in zebrafish neural tube patterning. Together our work should help explain how molecular and cellular mechanisms interact at multiple steps to ensure precise pattern formation. Such an integrated understanding is important for diagnosing and treating birth defects such as neural tube defects and in the rational design of engineered tissues.