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Noise drives sharpening of gene expression boundaries in the zebrafish hindbrain.

Zhang L, Radtke K, Zheng L, Cai AQ, Schilling TF, Nie Q - Mol. Syst. Biol. (2012)

Bottom Line: During development of rhombomeres in the zebrafish hindbrain, the morphogen retinoic acid (RA) induces expression of hoxb1a in rhombomere 4 (r4) and krox20 in r3 and r5.Computational analysis of spatial stochastic models shows, surprisingly, that noise in hoxb1a/krox20 expression actually promotes sharpening of boundaries between adjacent segments.This finding suggests a novel noise attenuation mechanism that relies on intracellular noise to induce switching and coordinate cellular decisions during developmental patterning.

View Article: PubMed Central - PubMed

Affiliation: Department of Mathematics, University of California, Irvine, CA 92697-3875, USA.

ABSTRACT
Morphogens provide positional information for spatial patterns of gene expression during development. However, stochastic effects such as local fluctuations in morphogen concentration and noise in signal transduction make it difficult for cells to respond to their positions accurately enough to generate sharp boundaries between gene expression domains. During development of rhombomeres in the zebrafish hindbrain, the morphogen retinoic acid (RA) induces expression of hoxb1a in rhombomere 4 (r4) and krox20 in r3 and r5. Fluorescent in situ hybridization reveals rough edges around these gene expression domains, in which cells co-express hoxb1a and krox20 on either side of the boundary, and these sharpen within a few hours. Computational analysis of spatial stochastic models shows, surprisingly, that noise in hoxb1a/krox20 expression actually promotes sharpening of boundaries between adjacent segments. In particular, fluctuations in RA initially induce a rough boundary that requires noise in hoxb1a/krox20 expression to sharpen. This finding suggests a novel noise attenuation mechanism that relies on intracellular noise to induce switching and coordinate cellular decisions during developmental patterning.

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A larger noise frequency ratio improves boundary sharpening. (A–C) Two-dimensional simulations of hoxb1a/krox20 gene expression at T=50 for the ratio of the frequency of noise in RA over the frequency of noise in gene expression at three different values: (A) γ=0.01; (B) γ=1; (C) γ=100 (hoxb1a: blue; krox20: red). (D) Sharpness Index versus frequency ratio.
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f5: A larger noise frequency ratio improves boundary sharpening. (A–C) Two-dimensional simulations of hoxb1a/krox20 gene expression at T=50 for the ratio of the frequency of noise in RA over the frequency of noise in gene expression at three different values: (A) γ=0.01; (B) γ=1; (C) γ=100 (hoxb1a: blue; krox20: red). (D) Sharpness Index versus frequency ratio.

Mentions: If boundary sharpening depends on gene switching induced by noise in gene expression, then the timing of switching, which is closely related to noise frequency, is likely to be critical. To test this, we have varied noise frequency, both in RA levels and in gene expression, to study effects on boundary sharpening. γ is defined as the ratio of frequency of noise in RA levels over that of gene expression. For a small γ, indicating high frequency noise in gene expression, rough boundaries remain rough (Figure 5A). In this case, gene expression oscillates relatively too fast to reach a critical level of gene switching to enable sharpening. Lower frequency noise in gene expression improves boundary sharpening (Figure 5B). Conversely, high frequency noise in RA (i.e., a larger γ) leads to better noise attenuation (Figure 5C) since the time average of RA signal over a substantial period reduces the influence of noise. As a result, the Sharpness Index, S, decreases as the frequency ratio γ increases, indicating that lower frequency noise in gene expression and higher frequency noise in RA together facilitate boundary sharpening (Figure 5D).


Noise drives sharpening of gene expression boundaries in the zebrafish hindbrain.

Zhang L, Radtke K, Zheng L, Cai AQ, Schilling TF, Nie Q - Mol. Syst. Biol. (2012)

A larger noise frequency ratio improves boundary sharpening. (A–C) Two-dimensional simulations of hoxb1a/krox20 gene expression at T=50 for the ratio of the frequency of noise in RA over the frequency of noise in gene expression at three different values: (A) γ=0.01; (B) γ=1; (C) γ=100 (hoxb1a: blue; krox20: red). (D) Sharpness Index versus frequency ratio.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3472692&req=5

f5: A larger noise frequency ratio improves boundary sharpening. (A–C) Two-dimensional simulations of hoxb1a/krox20 gene expression at T=50 for the ratio of the frequency of noise in RA over the frequency of noise in gene expression at three different values: (A) γ=0.01; (B) γ=1; (C) γ=100 (hoxb1a: blue; krox20: red). (D) Sharpness Index versus frequency ratio.
Mentions: If boundary sharpening depends on gene switching induced by noise in gene expression, then the timing of switching, which is closely related to noise frequency, is likely to be critical. To test this, we have varied noise frequency, both in RA levels and in gene expression, to study effects on boundary sharpening. γ is defined as the ratio of frequency of noise in RA levels over that of gene expression. For a small γ, indicating high frequency noise in gene expression, rough boundaries remain rough (Figure 5A). In this case, gene expression oscillates relatively too fast to reach a critical level of gene switching to enable sharpening. Lower frequency noise in gene expression improves boundary sharpening (Figure 5B). Conversely, high frequency noise in RA (i.e., a larger γ) leads to better noise attenuation (Figure 5C) since the time average of RA signal over a substantial period reduces the influence of noise. As a result, the Sharpness Index, S, decreases as the frequency ratio γ increases, indicating that lower frequency noise in gene expression and higher frequency noise in RA together facilitate boundary sharpening (Figure 5D).

Bottom Line: During development of rhombomeres in the zebrafish hindbrain, the morphogen retinoic acid (RA) induces expression of hoxb1a in rhombomere 4 (r4) and krox20 in r3 and r5.Computational analysis of spatial stochastic models shows, surprisingly, that noise in hoxb1a/krox20 expression actually promotes sharpening of boundaries between adjacent segments.This finding suggests a novel noise attenuation mechanism that relies on intracellular noise to induce switching and coordinate cellular decisions during developmental patterning.

View Article: PubMed Central - PubMed

Affiliation: Department of Mathematics, University of California, Irvine, CA 92697-3875, USA.

ABSTRACT
Morphogens provide positional information for spatial patterns of gene expression during development. However, stochastic effects such as local fluctuations in morphogen concentration and noise in signal transduction make it difficult for cells to respond to their positions accurately enough to generate sharp boundaries between gene expression domains. During development of rhombomeres in the zebrafish hindbrain, the morphogen retinoic acid (RA) induces expression of hoxb1a in rhombomere 4 (r4) and krox20 in r3 and r5. Fluorescent in situ hybridization reveals rough edges around these gene expression domains, in which cells co-express hoxb1a and krox20 on either side of the boundary, and these sharpen within a few hours. Computational analysis of spatial stochastic models shows, surprisingly, that noise in hoxb1a/krox20 expression actually promotes sharpening of boundaries between adjacent segments. In particular, fluctuations in RA initially induce a rough boundary that requires noise in hoxb1a/krox20 expression to sharpen. This finding suggests a novel noise attenuation mechanism that relies on intracellular noise to induce switching and coordinate cellular decisions during developmental patterning.

Show MeSH
Related in: MedlinePlus