Using cutting-edge imaging technology, University of California, Irvine biologists have determined that uncontrolled fluctuations (known at “noise) in the concentration of the vitamin A derivative Retinoic acid (RA) can lead to disruptions in brain organization during development.
By identifying how a cell responds to a signal made by another cell despite the level of noise present, the work may improve our understanding of developmental disorders.
Thomas F. Schilling, professor of developmental & cell biology, and his colleagues, published this study online at eLife.
During development, RA is an important secreted molecule that aids in the proper organization of the brain. The cellular response to RA depends upon its concentration, which is determined by its production, movement through tissue and interactions with many proteins within the cell. During normal development, cells can filter the “noise” in RA levels and establish appropriate brain organization. Schilling and study lead author Julian Sosnik wanted to measure the fluctuations in RA and determine how cells respond to the proper amount 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 one protein within developing cells that interacts with RA to help reduce the noise. When this protein was altered, cells could no longer control the level of noise within the RA gradient, which led to disruptions in brain organization.
With this, the researchers concluded that noise reduction within cells is critical for the proper response to the RA gradient and normal organization of the brain.
Future studies will employ new transgenic technologies to examine levels of noise in the expression of genes responding to RA in developing brain cells and address potential beneficial roles for noise in helping switch cells from one type to another in this system.
Other researchers who contributed to the study are Likun Zheng, Christopher V. Rackauckas, Michelle Digman, Enrico Gratton and Qing Nie.
Funding: This work was partly supported by grants from the NIH/NIGMS (R01-GM107264) and (P50-GM76516).
Source: UC Irvine
Image Credit: The image is in the public domain.
Original Research: Full open access research for “Noise modulation in retinoic acid signaling sharpens segmental boundaries of gene expression in the embryonic zebrafish hindbrain” by Julian Sosnik, Likun Zheng, Christopher V Rackauckas, Michelle Digman, Enrico Gratton, Qing Nie, and Thomas F Schilling in eLife. Published online April 12 2016 doi:10.7554/eLife.14034
Noise modulation in retinoic acid signaling sharpens segmental boundaries of gene expression in the embryonic zebrafish hindbrain
Morphogen gradients induce sharply defined domains of gene expression in a concentration-dependent manner, yet how cells interpret these signals in the face of spatial and temporal noise remains unclear. Using fluorescence lifetime imaging microscopy (FLIM) and phasor analysis to measure endogenous retinoic acid (RA) directly in vivo, we have investigated the amplitude of noise in RA signaling, and how modulation of this noise affects patterning of hindbrain segments (rhombomeres) in the zebrafish embryo. We demonstrate that RA forms a noisy gradient during critical stages of hindbrain patterning and that cells use distinct intracellular binding proteins to attenuate noise in RA levels. Increasing noise disrupts sharpening of rhombomere boundaries and proper patterning of the hindbrain. These findings reveal novel cellular mechanisms of noise regulation, which are likely to play important roles in other aspects of physiology and disease.
“Noise modulation in retinoic acid signaling sharpens segmental boundaries of gene expression in the embryonic zebrafish hindbrain” by Julian Sosnik, Likun Zheng, Christopher V Rackauckas, Michelle Digman, Enrico Gratton, Qing Nie, and Thomas F Schilling in eLife. Published online April 12 2016 doi:10.7554/eLife.14034