Too much 'noise' can affect brain development
Biologists have determined that uncontrolled fluctuations (or "noise) in the derivative of vitamin A , Retinoic acid (RA), can disrupt brain development.
Animal cells communicate with each other by releasing molecular signals that circulate between cells of developing tissues. These signals are detected by receptors on a cell's surface. Random variations in these signals (noise) can affect how many signals, how they move through the space between cells, where they bind to receptors, all making cell signalling very complex.
Cells responding to any particular signal somehow can ignore the noise of random variations to establish sharp boundaries between different cell types. This ability is needed for cells to maintain their distinct roles. However, few studies have attempted to measure the noise from random variations, or determine how cells manage to respond in a consistent manner and form specific tissues, without being confused by noise.
Retinoic acid is a signaling molecule important in the world of cell communication. Particularly in the development of the brain in animals.
RA forms a gradient along the body of an embryo from head to tail, an Anterior to Posterior axis (A-P). But its quantity in types of interactions has been difficult to measure. Julian Sosnik and Thomas F Schilling from the Department of Developmental and Cell Biology, University of California, Irvine, in the Center for Complex Biological Systems, exploited a way to measure the weak fluorescense given off by RA to detect and measure it in zebrafish embryos.
In order to establish the frequency of RA noise in zebrafish, they captured data from different cells, searching for RA lags which correlated with changes in cell function. Their experiments revealed that retinoic acid forms a gradient along zebra fish embryos, with lower levels at the head and higher levels at the tail.
They identified one protein, Crabp2a, within developing embryos that interacts with RA to reduce the noise from random variations. Crabp2a appears to control noise in RA levels quickly by binding to RA and helping it enter cells or by buffering its availability in the cell cytoplasm. When the Crabp2a protein was altered, cells could no longer control the level of RA noise — which led to disrupted brain organization.
[Crabp2a and Cyp26a1 are Retinoic acid receptors (RARs) and often act to repress transcription until they bind with RA. Therefore Crabp2a and Cyp26a1 appeart to modulate noise in RA targets by altering this balance between activation and repression of gene transcription.]
These mechanisms for binding RA are likely to be similar in other cell signaling systems as they are critical to embryo development and general adult physiology, and also possibly to human diseases.
The results of their study are published online at eLife, in which the researchers conclude that noise reduction within cells is critical for the proper response to the RA gradient and normal organization of brain tissue.
Future studies will continue to examine how noise affects the expression of genes responding to RA in developing brain cells. There may be potential benefit in knowing how noise changes cells from one type to another.
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.
Other researchers who contributed to the study are Likun Zheng, Christopher V. Rackauckas, Michelle Digman, Enrico Gratton and Qing Nie. This work was partly supported by grants from the NIH/NIGMS (R01-GM107264) and (P50-GM76516).
Nature Reviews: Genetic
Retinoic acid in development: towards an integrated view
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