Using cutting-edge imaging technology, Professor Thomas F. Schilling, Developmental and Cell Biology, and colleagues, have determined that uncontrolled fluctuations (known as “noise”) in the concentration of the vitamin A derivative retinoic acid (RA) can lead to disruptions in brain organization during development. Identifying how a cell responds to a signal made by another cell, despite the level of noise present, may improve our understanding of developmental disorders.
During development, RA is an important molecule secreted to aid in the proper organization of the brain. The cellular response to RA is dependent upon its concentration, which is determined by its production, movement through tissue and interactions with other proteins within the cell. During normal development, cells can ignore the “noise” in the RA levels and establish appropriate brain organization. Professor Schilling and lead author Dr. Julian Sosnik wanted to determine how cells respond to the proper amount of RA despite the presence of constant noise.
To accomplish this, they used Fluorescence Lifetime Imaging to exploit the auto-fluorescent nature of RA and measure its distribution across the developing zebrafish embryo. The team found that RA forms a gradient in the embryo, with a lower concentration at the head. They also observed that a large amount of “noise” exists within the RA gradient. They identified a protein within developing cells that interacts with RA to help reduce the noise. When the protein was altered, cells could no longer control the level of noise within the RA gradient, which led to disruptions in brain organization. They concluded that noise reduction within cells is critical for the proper response to the RA gradient and normal organization of the brain.
Other researchers who contributed to the study were: Likun Zheng, Christopher V. Rackauckas, Michelle Digman, Enrico Gratton, and Qing Nie. The full study can be found online at eLIFE.