Too Much ‘Noise’ Is Bad For Brain Development, Biologists Studying Retinoic Acid Say

Biologists at the University of California, Irvine, have determined that too much uncontrolled fluctuations (known as noise) in the concentration of the vitamin A derivative Retinoic acid leads to disruptions in organization of the brain during development. The team, led by Thomas F. Schilling, Professor of Developmental & Cell Biology and lead author Julian Sosnik, published their study online at eLife.

“Animal cells need to be able to communicate with each other so that they can work together in tissues and organs. To do so, cells release signaling molecules that can move around within a tissue and be detected by receptors on other cells.”

Retinoic acid (RA) is an important molecule that helps the brain organize itself properly. During normal brain development, cells can filter the “noise” in RA levels and organize the brain properly. Schilling and Sosnik decided to measure the fluctuations in RA, specifically the amplitude of noise in RA signaling, to see how cells respond to the proper amount regardless of the presence of constant noise. They used fluorescence lifetime imaging “to exploit the auto-fluorescent nature of RA and measure its distribution” in a developing zebrafish embryo, according to Science Daily. The biologists say that noise is inherent in biological systems, but until recently scientists lacked the tools to study it in vivo.

“We tend to assume that the signaling molecules are evenly distributed across a tissue and affect all the receiving cells in the same way. However, random variations (noise) that affect how many of these molecules are produced, how they move through the space between cells and how they bind to receptors makes the reality much more complex. Cells responding to the signal somehow can ignore this noise and establish sharp boundaries between different cell types so that neighboring cells have distinct roles in the tissue. Few studies have attempted to measure such noise or address how cells manage to respond to noisy signals in a consistent manner.”

They determined that RA creates a gradient in the zebrafish and a lower concentration at the head of the zebrafish. The authors said that they were able to observe that a large amount of noise exists within this RA gradient. They also found that a particular protein that can be found inside developing cells that work with RA to help reduce the noise, but if the protein is changed, the cells can’t control the level of noise within the RA gradient. When this happens, the researchers said that they saw disruptions in brain organization.

The biologists say that for the normal organization of the brain and the proper response to the RA gradient, noise reduction within cells is critical.

Dr. Schilling notes his research areas of interest include zebrafish, retinoic acid, pattern formation, embryogenesis, and morphogenesis. His lab has an online blog which announced the research paper written by Julian Sosnik, Likun Zheng, Christopher Rackauckas, Michelle Digman, Enrico Gratton, Qing Nie, and himself.

Zebrafish are a preferred research model because all proteins of zebrafish studied so far have a similar function as they would in mammals, they are easier to house than rodents, their embryos are completely transparent, and they have lots of offspring. Just one pair of zebrafish can produce up to 300 fertilized eggs every week, allowing scientists to have significant numbers of test samples that quickly develop into adult fish.

Fluorescence lifetime imaging, which was the technology the team of biologists used to exploit the auto-fluorescent nature of RA and measure its distribution, is a fluorescence imaging technique that is based on the lifetime of individual fluorophores instead of their emission spectra.

[Image via Pixabay]