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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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Growth of the embryo delays boundary sharpening. (A) Mean values of the intracellular RA gradient along the X axis at different times, showing a growth-dependent fading of RA levels (see one sample of two-dimensional RA gradients in Supplementary Figure S9A). (B) The pattern of hoxb1a/krox20 gene expression during growth (hoxb1a: blue; krox20: red).
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f6: Growth of the embryo delays boundary sharpening. (A) Mean values of the intracellular RA gradient along the X axis at different times, showing a growth-dependent fading of RA levels (see one sample of two-dimensional RA gradients in Supplementary Figure S9A). (B) The pattern of hoxb1a/krox20 gene expression during growth (hoxb1a: blue; krox20: red).

Mentions: Because tissue growth potentially changes the RA gradient and affects the pattern, we also explore a two-dimensional stochastic model incorporating growth along the A-P axis. As measured in our fluorescent in situs (Figure 1), the length of the r3-r5 field increases from 106±4 μm at 10.7 h.p.f. to 127±11 μm at 12.7 h.p.f., corresponding to approximately a 20% increase in A-P length. When incorporated into the stochastic PDE model (see Section 1.3 in Supplementary information), simulations reveal that as the RA gradient fades due to growth (Figure 6A) sharpening of the r4/5 boundary is delayed and less accurate (Figure 6B). This reflects dependence of gene switching on RA concentration—lower RA levels reduce the switching probability for cells around the future boundary. Furthermore, without noise in the gene expression, a fading RA due to growth becomes unable to induce sharp boundaries of gene expression, indicating that this noise is essential (Supplementary Figure S9).


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)

Growth of the embryo delays boundary sharpening. (A) Mean values of the intracellular RA gradient along the X axis at different times, showing a growth-dependent fading of RA levels (see one sample of two-dimensional RA gradients in Supplementary Figure S9A). (B) The pattern of hoxb1a/krox20 gene expression during growth (hoxb1a: blue; krox20: red).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: Growth of the embryo delays boundary sharpening. (A) Mean values of the intracellular RA gradient along the X axis at different times, showing a growth-dependent fading of RA levels (see one sample of two-dimensional RA gradients in Supplementary Figure S9A). (B) The pattern of hoxb1a/krox20 gene expression during growth (hoxb1a: blue; krox20: red).
Mentions: Because tissue growth potentially changes the RA gradient and affects the pattern, we also explore a two-dimensional stochastic model incorporating growth along the A-P axis. As measured in our fluorescent in situs (Figure 1), the length of the r3-r5 field increases from 106±4 μm at 10.7 h.p.f. to 127±11 μm at 12.7 h.p.f., corresponding to approximately a 20% increase in A-P length. When incorporated into the stochastic PDE model (see Section 1.3 in Supplementary information), simulations reveal that as the RA gradient fades due to growth (Figure 6A) sharpening of the r4/5 boundary is delayed and less accurate (Figure 6B). This reflects dependence of gene switching on RA concentration—lower RA levels reduce the switching probability for cells around the future boundary. Furthermore, without noise in the gene expression, a fading RA due to growth becomes unable to induce sharp boundaries of gene expression, indicating that this noise is essential (Supplementary Figure S9).

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