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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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Modeling induction of hoxb1a and krox20 expression by a gradient of retinoic acid (RA) in a noise-free system. (A) Diagram illustrating RA movement from extracellular [RA]out to intracellular [RA]in, self-enhanced degradation via Cyp26a1, and induction of hoxb1a and krox20 which undergo auto-activation and cross-inhibition. (B) In the absence of noise, a smooth RA gradient leads to sharp boundaries of gene expression—as long as there is a low initial level of hoxb1a (∼0.1). (C) Three-dimensional graph of krox20 (gk, Y axis) and hoxb1a (gh, Z axis) expression levels at different points along the RA gradient (X axis). The number of possible gene states is 5 (0<[RA]in<0.22), 3 (0.22<[RA]in<0.85), and 1 ([RA]in>0.85) for a normalized RA concentration. (D) Phase diagram of Hoxb1 (red) and Krox20 (blue) activation illustrating effects of the initial level of Hoxb1 (Y axis) at different segmental positions (X axis). The initial level of krox20 is zero and the RA gradient used to generate the diagram is shown in (B).
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f2: Modeling induction of hoxb1a and krox20 expression by a gradient of retinoic acid (RA) in a noise-free system. (A) Diagram illustrating RA movement from extracellular [RA]out to intracellular [RA]in, self-enhanced degradation via Cyp26a1, and induction of hoxb1a and krox20 which undergo auto-activation and cross-inhibition. (B) In the absence of noise, a smooth RA gradient leads to sharp boundaries of gene expression—as long as there is a low initial level of hoxb1a (∼0.1). (C) Three-dimensional graph of krox20 (gk, Y axis) and hoxb1a (gh, Z axis) expression levels at different points along the RA gradient (X axis). The number of possible gene states is 5 (0<[RA]in<0.22), 3 (0.22<[RA]in<0.85), and 1 ([RA]in>0.85) for a normalized RA concentration. (D) Phase diagram of Hoxb1 (red) and Krox20 (blue) activation illustrating effects of the initial level of Hoxb1 (Y axis) at different segmental positions (X axis). The initial level of krox20 is zero and the RA gradient used to generate the diagram is shown in (B).

Mentions: RA activates hoxb1a expression in r4 (directly) and krox20 in r3 and r5 (indirectly through Vhnf1 and MafB) in a concentration-dependent manner (Niederreither et al, 2000; Begemann et al, 2001; Hernandez et al, 2004; Labalette et al, 2011). Our deterministic model is based on a previous continuum model of the RA signaling network that consists of diffusive extracellular and intracellular RA, and self-enhanced degradation through the enzyme Cyp26a1 (White et al, 2007), without inclusion of downstream signal responses (see Equation S1.1 in Supplementary information). In the new model, RA activates hoxb1a and krox20 expression, which in turn both positively regulate their own expression and negatively regulate each other (Barrow et al, 2000; Giudicelli et al, 2001; Alexander et al, 2009; Figure 2A). Such positive auto-regulation and mutual inhibition have been modeled and shown to result in only one gene remaining active in a particular cell (Meinhardt, 1978, 1982). Here, the dynamics of both genes are modeled using rate equations along with Hill functions for regulation, with RA as input (see Equation S1.2 in Supplementary information).


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)

Modeling induction of hoxb1a and krox20 expression by a gradient of retinoic acid (RA) in a noise-free system. (A) Diagram illustrating RA movement from extracellular [RA]out to intracellular [RA]in, self-enhanced degradation via Cyp26a1, and induction of hoxb1a and krox20 which undergo auto-activation and cross-inhibition. (B) In the absence of noise, a smooth RA gradient leads to sharp boundaries of gene expression—as long as there is a low initial level of hoxb1a (∼0.1). (C) Three-dimensional graph of krox20 (gk, Y axis) and hoxb1a (gh, Z axis) expression levels at different points along the RA gradient (X axis). The number of possible gene states is 5 (0<[RA]in<0.22), 3 (0.22<[RA]in<0.85), and 1 ([RA]in>0.85) for a normalized RA concentration. (D) Phase diagram of Hoxb1 (red) and Krox20 (blue) activation illustrating effects of the initial level of Hoxb1 (Y axis) at different segmental positions (X axis). The initial level of krox20 is zero and the RA gradient used to generate the diagram is shown in (B).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Modeling induction of hoxb1a and krox20 expression by a gradient of retinoic acid (RA) in a noise-free system. (A) Diagram illustrating RA movement from extracellular [RA]out to intracellular [RA]in, self-enhanced degradation via Cyp26a1, and induction of hoxb1a and krox20 which undergo auto-activation and cross-inhibition. (B) In the absence of noise, a smooth RA gradient leads to sharp boundaries of gene expression—as long as there is a low initial level of hoxb1a (∼0.1). (C) Three-dimensional graph of krox20 (gk, Y axis) and hoxb1a (gh, Z axis) expression levels at different points along the RA gradient (X axis). The number of possible gene states is 5 (0<[RA]in<0.22), 3 (0.22<[RA]in<0.85), and 1 ([RA]in>0.85) for a normalized RA concentration. (D) Phase diagram of Hoxb1 (red) and Krox20 (blue) activation illustrating effects of the initial level of Hoxb1 (Y axis) at different segmental positions (X axis). The initial level of krox20 is zero and the RA gradient used to generate the diagram is shown in (B).
Mentions: RA activates hoxb1a expression in r4 (directly) and krox20 in r3 and r5 (indirectly through Vhnf1 and MafB) in a concentration-dependent manner (Niederreither et al, 2000; Begemann et al, 2001; Hernandez et al, 2004; Labalette et al, 2011). Our deterministic model is based on a previous continuum model of the RA signaling network that consists of diffusive extracellular and intracellular RA, and self-enhanced degradation through the enzyme Cyp26a1 (White et al, 2007), without inclusion of downstream signal responses (see Equation S1.1 in Supplementary information). In the new model, RA activates hoxb1a and krox20 expression, which in turn both positively regulate their own expression and negatively regulate each other (Barrow et al, 2000; Giudicelli et al, 2001; Alexander et al, 2009; Figure 2A). Such positive auto-regulation and mutual inhibition have been modeled and shown to result in only one gene remaining active in a particular cell (Meinhardt, 1978, 1982). Here, the dynamics of both genes are modeled using rate equations along with Hill functions for regulation, with RA as input (see Equation S1.2 in Supplementary information).

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