Limits...
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.

Show MeSH

Related in: MedlinePlus

Effects of noise either in the RA gradient or in hoxb1a/krox20 expression alone on boundary sharpening. (A–C) With noise in RA alone, boundaries are initially rough and never sharpen. (D–F) With noise in hoxb1a/krox20 expression alone boundaries start out sharp at the outset and remain sharp. (A, D) Single samples at three time points illustrating gene expression levels (Y axis) at different A-P positions in r3-5 (X axis). (B, E) Gene expression distributions (Y axis) at different positions relative to the r4/5 boundary (X axis). Solutions are at the scaled time T=50, which is typically long enough for simulations to reach steady state (1000 samples are taken to calculate the gene distributions). (C, F) 2D simulations at three time points showing the pattern of hoxb1a/krox20 gene expression around the r4/5 boundary (hoxb1a: blue; krox20: red).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3472692&req=5

f3: Effects of noise either in the RA gradient or in hoxb1a/krox20 expression alone on boundary sharpening. (A–C) With noise in RA alone, boundaries are initially rough and never sharpen. (D–F) With noise in hoxb1a/krox20 expression alone boundaries start out sharp at the outset and remain sharp. (A, D) Single samples at three time points illustrating gene expression levels (Y axis) at different A-P positions in r3-5 (X axis). (B, E) Gene expression distributions (Y axis) at different positions relative to the r4/5 boundary (X axis). Solutions are at the scaled time T=50, which is typically long enough for simulations to reach steady state (1000 samples are taken to calculate the gene distributions). (C, F) 2D simulations at three time points showing the pattern of hoxb1a/krox20 gene expression around the r4/5 boundary (hoxb1a: blue; krox20: red).

Mentions: In contrast, if noise is introduced into the intracellular RA concentration, [RA]in (i.e., ), for example, due to fluctuations in RA transport into cells, then boundaries between hoxb1a and krox20 never sharpen (Figure 3A). In this case, the r3 domain of krox20 expression expands as fluctuations in the RA gradient reach the threshold that induces krox20. Monte Carlo simulations indicate that there is a large variation in the distribution of gene expression around the r4/5 boundary over time when [RA]in is noisy (Figure 3B). Two-dimensional simulations also show that hoxb1a and krox20 expression domains initially form a rough r4/5 boundary, which does not sharpen (Figure 3C). An initial noisy distribution of hoxb1a expression at this boundary can also disrupt sharpening (see Supplementary Figure S5). However, if noise is only restricted to later hoxb1a and krox20 expression, and not local RA concentration (i.e., ), then boundaries tend to sharpen from the outset (Figure 3D and F) and Monte Carlo simulations confirm this prediction (Figure 3E). These results suggest that rough boundaries of gene expression between r4 and r5 arise due to noise in [RA]in or initial hoxb1a expression.


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)

Effects of noise either in the RA gradient or in hoxb1a/krox20 expression alone on boundary sharpening. (A–C) With noise in RA alone, boundaries are initially rough and never sharpen. (D–F) With noise in hoxb1a/krox20 expression alone boundaries start out sharp at the outset and remain sharp. (A, D) Single samples at three time points illustrating gene expression levels (Y axis) at different A-P positions in r3-5 (X axis). (B, E) Gene expression distributions (Y axis) at different positions relative to the r4/5 boundary (X axis). Solutions are at the scaled time T=50, which is typically long enough for simulations to reach steady state (1000 samples are taken to calculate the gene distributions). (C, F) 2D simulations at three time points showing the pattern of hoxb1a/krox20 gene expression around the r4/5 boundary (hoxb1a: blue; krox20: red).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Effects of noise either in the RA gradient or in hoxb1a/krox20 expression alone on boundary sharpening. (A–C) With noise in RA alone, boundaries are initially rough and never sharpen. (D–F) With noise in hoxb1a/krox20 expression alone boundaries start out sharp at the outset and remain sharp. (A, D) Single samples at three time points illustrating gene expression levels (Y axis) at different A-P positions in r3-5 (X axis). (B, E) Gene expression distributions (Y axis) at different positions relative to the r4/5 boundary (X axis). Solutions are at the scaled time T=50, which is typically long enough for simulations to reach steady state (1000 samples are taken to calculate the gene distributions). (C, F) 2D simulations at three time points showing the pattern of hoxb1a/krox20 gene expression around the r4/5 boundary (hoxb1a: blue; krox20: red).
Mentions: In contrast, if noise is introduced into the intracellular RA concentration, [RA]in (i.e., ), for example, due to fluctuations in RA transport into cells, then boundaries between hoxb1a and krox20 never sharpen (Figure 3A). In this case, the r3 domain of krox20 expression expands as fluctuations in the RA gradient reach the threshold that induces krox20. Monte Carlo simulations indicate that there is a large variation in the distribution of gene expression around the r4/5 boundary over time when [RA]in is noisy (Figure 3B). Two-dimensional simulations also show that hoxb1a and krox20 expression domains initially form a rough r4/5 boundary, which does not sharpen (Figure 3C). An initial noisy distribution of hoxb1a expression at this boundary can also disrupt sharpening (see Supplementary Figure S5). However, if noise is only restricted to later hoxb1a and krox20 expression, and not local RA concentration (i.e., ), then boundaries tend to sharpen from the outset (Figure 3D and F) and Monte Carlo simulations confirm this prediction (Figure 3E). These results suggest that rough boundaries of gene expression between r4 and r5 arise due to noise in [RA]in or initial hoxb1a expression.

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