Article

Precision and scaling in morphogen gradient read-out

Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
Molecular Systems Biology (Impact Factor: 10.87). 03/2010; 6(1):351. DOI: 10.1038/msb.2010.7
Source: PubMed

ABSTRACT

Morphogen gradients infer cell fate as a function of cellular position. Experiments in Drosophila embryos have shown that the Bicoid (Bcd) gradient is precise and exhibits some degree of scaling. We present experimental results on the precision of Bcd target genes for embryos with a single, double or quadruple dose of bicoid demonstrating that precision is highest at mid-embryo and position dependent, rather than gene dependent. This confirms that the major contribution to precision is achieved already at the Bcd gradient formation. Modeling this dynamic process, we investigate precision for inter-embryo fluctuations in different parameters affecting gradient formation. Within our modeling framework, the observed precision can only be achieved by a transient Bcd profile. Studying different extensions of our modeling framework reveals that scaling is generally position dependent and decreases toward the posterior pole. Our measurements confirm this trend, indicating almost perfect scaling except for anterior most expression domains, which overcompensate fluctuations in embryo length.

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Available from: Aitana Neves, Jul 06, 2014
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    • "The mean B profiles from the large and small embryos converge upon each other as a function of relative AP position x/L (Fig. 1J). This convergence takes place in broad regions of the embryos along the AP axis (except the anterior) and is a hallmark of Bcd gradient scaling (He et al., 2008; de Lachapelle and Bergmann, 2010; Deng et al., 2010; Cheung et al., 2011). To evaluate this convergence or scaling better, we plotted the differences between the mean B values in these embryos, ΔB, as a function of either x or x/L (Fig. 2A and 2B, respectively). "
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    ABSTRACT: The formation of patterns that are proportional to the size of the embryo is an intriguing but poorly understood feature of development. Molecular mechanisms controlling such proportionality, or scaling, can be probed through quantitative interrogations of the properties of morphogen gradients that instruct patterning. Recent studies of the Drosophila morphogen gradient Bicoid (Bcd), which is required for anterior-posterior (AP) patterning in the early embryo, have uncovered two distinct ways of scaling. Whereas between-species scaling is achieved by adjusting the exponential shape characteristic of the Bcd gradient profile, namely, its length scale or length constant (λ), within-species scaling is achieved through adjusting the profile's amplitude, namely, the Bcd concentration at the anterior (B0). Here, we report a case in which Drosophila melanogaster embryos exhibit Bcd gradient properties uncharacteristic of their size. The embryos under investigation were from a pair of inbred lines that had been artificially selected for egg size extremes. We show that B0 in the large embryos is uncharacteristically low but λ is abnormally extended. Although the large embryos have more total bcd mRNA than their smaller counterparts, as expected, its distribution is unusually broad. We show that the large and small embryos develop gene expression patterns exhibiting boundaries that are proportional to their respective lengths. Our results suggest that the large-egg inbred line has acquired compensating properties that counteract the extreme length of the embryos to maintain Bcd gradient properties necessary for robust patterning. Our study documents, for the first time to our knowledge, a case of within-species Bcd scaling achieved through adjusting the gradient profile's exponential shape characteristic, illustrating at a molecular level how a developmental system can follow distinct operational paths towards the goal of robust and scaled patterning.
    Full-text · Article · Nov 2013 · Development
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    • "It has an expression domain in the anterior half of the embryo with a precise and scaled boundary position [14]. Importantly, scaling properties near the middle of the embryo (along the AP axis) are greatly influential to the patterning landscape along the entire AP length [19], [28]–[30]. The hb gene contains two promoters and three known enhancers that together orchestrate the dynamic expression patterns during development [24], [31]. "
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    ABSTRACT: Anterior-posterior (AP) patterning in the Drosophila embryo is dependent on the Bicoid (Bcd) morphogen gradient. However, most target genes of Bcd also require additional inputs to establish their expression domains, reflective of the operation of a cross-regulatory network and contributions of other maternal signals. This is in contrast to hunchback (hb), which has an anterior expression domain driven by an enhancer that appears to respond primarily to the Bcd input. To gain a better understanding of the regulatory logic of the AP patterning network, we perform quantitative studies that specifically investigate the dynamics of hb transcription during development. We show that Bcd-dependent hb transcription, monitored by the intron-containing nascent transcripts near the P2 promoter, is turned off quickly-on the order of a few minutes-upon entering the interphase of nuclear cycle 14A. This shutdown contrasts with earlier cycles during which active hb transcription can persist until the moment when the nucleus enters mitosis. The shutdown takes place at a time when the nuclear Bcd gradient profile in the embryo remains largely intact, suggesting that this is a process likely subject to control of a currently unknown regulatory mechanism. We suggest that this dynamic feature offers a window of opportunity for hb to faithfully interpret, and directly benefit from, Bcd gradient properties, including its scaling properties, to help craft a robust AP patterning outcome.
    Full-text · Article · Apr 2013 · PLoS ONE
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    • "Bcd is a transcriptional activator that binds to the enhancers of its target genes such as hunchback (hb) and activates their transcription [5], [9], [17], [23]. The mechanisms of sensing the concentrations of morphogen molecules by a gene or cell are crucial to our knowledge of how the positional information provided by a morphogen gradient is decoded during development [24]–[26]. Theoretical studies suggest that there are fundamental limits to the time period necessary for a cell or gene to accurately “sense” or “read” the differences in morphogen concentrations to make a response to form a desired expression boundary [27], [28]. This time period is dependent on, among other things, both the diffusion constant and the nuclear concentration of Bcd at the boundary position. "
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    ABSTRACT: The Drosophila blastoderm embryo undergoes rapid cycles of nuclear division. This poses a challenge to genes that need to reliably sense the concentrations of morphogen molecules to form desired expression patterns. Here we investigate whether the transcriptional state of hunchback (hb), a target gene directly activated by the morphogenetic protein Bicoid (Bcd), exhibits properties indicative of inheritance between mitotic cycles. To achieve this, we build a dataset of hb transcriptional states at the resolution of individual nuclei in embryos at early cycle 14. We perform a spatial point pattern (SPP) analysis to evaluate the spatial relationships among the nuclei that have distinct numbers of hb gene copies undergoing active transcription in snapshots of embryos. Our statistical tests and simulation studies reveal properties of dispersed clustering for nuclei with both or neither copies of hb undergoing active transcription. Modeling of nuclear lineages from cycle 11 to cycle 14 suggests that these two types of nuclei can achieve spatial clustering when, and only when, the transcriptional states are allowed to propagate between mitotic cycles. Our results are consistent with the possibility where the positional information encoded by the Bcd morphogen gradient may not need to be decoded de novo at all mitotic cycles in the Drosophila blastoderm embryo.
    Full-text · Article · Apr 2013 · PLoS ONE
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