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Developmental biology - In Silico/In Vivo Embryology

Noise Cancellation Molds Tissues

Researchers uncover how noise cancellation sculpts tissues and organs during embryogenesis...

Noise is usually considered a nuisance as it prevents us from hearing what others are saying. But in biology, the physical differences between two organisms of the same species, two humans for example, are the result of so-called developmental noise - collisions between molecules in cells reacting to environmental conditions early in an organism's growth.

Generally, mechanisms are in place to prevent biological noise from incorrect development in an organism. Now, Makoto Sato and colleagues from Kanazawa University, have discovered one biochemical signaling pathway which acts as a noise cancelling system when the differentiation process between neural stem cells is going on - these are the self-renewing cells that play an important part in developing an embryo's nervous system. Their work is published in Scientific Reports.

The fruit fly was the model organism used to examine the noise cancellation mechanism. Researchers looked at its visual system for propagation of a 'pro-neural wave' of cells. This occurs when neuroepithelial cells differentiate into neuroblasts - cells on their way to becoming neurons.

Inspired by their earlier research, Sato and colleagues hypothesized a chain reaction known as JAK/STAT that occurs between proteins, acts as noise cancellation. Combining mathematical models with genetic experiments, they designed a set of equations to measure how variations in the JAK/STAT system produce a pro-neural wave of sound. They found that by including JAK/STAT signaling in their measurements, spontaneous, noise-induced neuroblast differentiation was stopped.

To confirm the effect of JAK/STAT signals in living organisms, researchers conducted experiments where that signaling pathway was reduced. When reduced, an incremental gradient descent of neuroblasts was seen consistent with the idea that JAK/STAT has a noise-canceling function. More Genetic experiments produced more details on how JAK/STAT noise canceling happens and that it may be a mechanism conserved throughout evolution.

Sato's group contributes to our understanding of noise-canceling mechanisms in developmental biology, while also stressing the power of combining 'in silico' (computational models) with 'in vivo' (living) studies. According to the scientists, "by applying a combination of mathematical modeling and molecular genetics, we can solve biological questions that have previously been difficult to address."

Organismal development is precisely regulated by a sequence of gene functions even in the presence of biological noise. However, it is difficult to evaluate the effect of noise in vivo, and the mechanisms by which noise is filtered during development are largely unknown. To identify the noise-canceling mechanism, we used the fly visual system, in which the timing of differentiation of neural stem cells is spatio-temporally ordered. Our mathematical model predicts that JAK/STAT signaling contributes to noise canceling to guarantee the robust progression of the differentiation wave in silico. We further demonstrate that the suppression of JAK/STAT signaling causes stochastic and ectopic neural stem cell differentiation in vivo, suggesting an evolutionarily conserved function of JAK/STAT to regulate the robustness of stem cell differentiation.


We thank Rie Takayama and members of Sato lab for supporting fly work, and H. J. Bellen, Bloomington Drosophila Stock Center (BDSC), Vienna Drosophila Stock Center, Drosophila Genetic Resource Center, Kyoto, for flies and antibodies. This work was supported by CREST (JPMJCR14D3 to M.S. and S.E.) from JST, Grant-in-Aid for Scientific Research on Innovative Areas (JP17H05739 to M.S., JP17H05761 to M.S., and JP18H05099 to T.Y.), Grant-in-Aid for Scientific Research (B) (JP17H03542 to M.S. and JP16H03949 to M.N.), and Grant-in-Aid for Young Scientists (B) (JP17K14228 to Y.T.) from MEXT, Takeda Science Foundation (to M.S.), and Cooperative Research of ‘Network Joint Research Center for Materials and Devices’ (to M.S. and M.N.).

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Sep 17, 2018   Fetal Timeline   Maternal Timeline   News   News Archive

Capturing the pro-neural [prior to formation of a neuron] wave in cells
of the embryonic fruit fly visual system. Photo: Kanawaza University.

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