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Review
. 2015 Dec 1;142(23):3996-4009.
doi: 10.1242/dev.129452.

Morphogen Rules: Design Principles of Gradient-Mediated Embryo Patterning

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Free PMC article
Review

Morphogen Rules: Design Principles of Gradient-Mediated Embryo Patterning

James Briscoe et al. Development. .
Free PMC article

Abstract

The Drosophila blastoderm and the vertebrate neural tube are archetypal examples of morphogen-patterned tissues that create precise spatial patterns of different cell types. In both tissues, pattern formation is dependent on molecular gradients that emanate from opposite poles. Despite distinct evolutionary origins and differences in time scales, cell biology and molecular players, both tissues exhibit striking similarities in the regulatory systems that establish gene expression patterns that foreshadow the arrangement of cell types. First, signaling gradients establish initial conditions that polarize the tissue, but there is no strict correspondence between specific morphogen thresholds and boundary positions. Second, gradients initiate transcriptional networks that integrate broadly distributed activators and localized repressors to generate patterns of gene expression. Third, the correct positioning of boundaries depends on the temporal and spatial dynamics of the transcriptional networks. These similarities reveal design principles that are likely to be broadly applicable to morphogen-patterned tissues.

Keywords: Bicoid; Drosophila blastoderm; Gene regulatory network; Morphogen interpretation; Sonic hedgehog; Vertebrate neural tube.

Conflict of interest statement

Competing interests

The authors declare no competing or financial interests.

Figures

Fig. 1.
Fig. 1.
Design principles of patterning in the Drosophila blastoderm and vertebrate neural tube. (A) Signaling gradients polarize tissues by initiating and orienting gene expression patterns. A morphogen (M, left), Bcd in the case of the blastoderm (center) and Shh for the neural tube (right), forms a gradient. This asymmetry initiates the division of the tissue into domains of gene expression (colored blocks) arrayed along the patterning axis (anterior-posterior in the blastoderm and ventral-dorsal in the neural tube). (B) Patterns of target gene expression are controlled by modular regulatory elements containing binding sites for multiple distinct TFs. These elements integrate transcription inputs from morphogen effectors, uniformly expressed factors, and the transcriptional repressors that comprise the morphogen-regulated transcriptional network. (C) The dynamics of the transcriptional network transform broadly distributed activation and localized repression mechanisms into precisely positioned boundaries of gene expression. This directly links spatial and temporal mechanisms of pattern formation.
Fig. 2.
Fig. 2.
Target gene expression boundaries do not correlate with simple concentration thresholds. (A) Boundaries of the Bcd target genes otd and hb are set at specific positions in wild-type (wt; 2× Bcd) embryos. Neither gene is expressed in embryos laid by bcd mutant (bcd−/−) females. When the Bcd gradient is flattened by genetic manipulation, the expression of otd and hb is restored but otd expression shows a sharp boundary that shifts posteriorly when bcd copy number is increased from two to six. By contrast, hb is expressed throughout the embryo in response to the flattened Bcd gradient. In embryos with flattened gradients, both otd and hb can be activated by lower concentrations of Bcd than those associated with their boundary positions in wild-type embryos. (B) Drosophila embryos with altered Bcd dosage (x-axis) show shifts in target gene boundary positions (y-axis), but these (red line) are smaller than predicted by a linear relationship between Bcd dose and boundary position (dashed line). (C) In the neural tube, progenitor identities (upper images) are established sequentially, with identities corresponding to higher morphogen concentrations appearing after longer periods of signaling. As a consequence, ventral progenitors exposed to high concentrations of Shh transiently adopt a gene expression profile associated with fates induced by lower concentrations. Measurements of Gli activity (bottom images, purple gradient) indicate that the amplitude and range of the gradient change over time. The level of Gli activity initially increases before decreasing, creating an adapting response. Correlating Gli activity levels with individual expression boundaries indicates that a boundary of gene expression is associated with different levels of Gli activity at different developmental times.
Fig. 3.
Fig. 3.
The cis-regulatory mechanisms controlling gene expression. (A) A simple mechanism of morphogen gene regulation is that target gene boundary position is determined directly by the binding affinity of CREs for the morphogen effector. The affinity of the CRE thus determines the amount of activated morphogen effector (purple) bound and is predicted to correlate with the extent of gene expression. High-affinity sites (red) produce long-range induction, whereas low-affinity binding sites (green) result in more restricted gene induction. Increasing the affinity of these binding sites (dotted green) would expand the range of gene induction. (B) There is a lack of correlation between boundary positions (x-axis) of a set of Bcd target genes (blue points) and the affinity of Bcd binding sites (y-axis) in the CREs associated with the target genes. (C) The CREs of target genes within the patterning network combine three classes of transcriptional inputs. The morphogen effectors (M, purple) act broadly to regulate many target genes along their patterning axis. Input from uniformly expressed factors (U, yellow) change the sensitivity of individual target genes to morphogen input. Repressive input from pd-TFs (TF1 and TF2) regulated by the network inhibit the positive activity of the morphogen and uniform factors. The integration of these inputs produces the regulatory logic of the transcriptional network. (D) Patterning by combinatorial binding in the blastoderm. The expression patterns of two activators (Bcd and Zld) and two repressors (Slp1 and Run) are shown (left). Hypothetical CREs are also shown (center) with their predicted expression patterns (right). The top construct contains only activation inputs and is expressed throughout the anterior embryo. The addition of repressor sites restricts activation to specific regions and positions the boundaries of gene expression. (E) Nkx6.1 is expressed in the ventral third of the neural tube. An Nkx6.1 CRE recapitulates this expression and contains a combination of binding sites for Gli, Sox2 and the pd-TFs Dbx and Msx. In the ventral neural tube, the absence of repressor forms of Gli and the lack of Dbx and Msx expression allows Sox2 proteins to activate the CRE. Dorsal to this, the presence of Gli repressors and Dbx or Msx blocks the activity of the CRE. GliA and GliR, activator and repressor forms of Gli.
Fig. 4.
Fig. 4.
The dynamics of the transcriptional network generate pattern. (A) A mathematical model of the gap gene network recapitulates the temporal-spatial pattern along the AP axis of the blastoderm. Cross-regulatory interactions between gap gene pairs establish the initial patterns of pd-TF expression in middle regions of the embryo (65% to 29% embryo length) (time 1). Asymmetries in the strength of cross-repression between gap genes means that posterior gap genes dominate over their more anterior partners. As development proceeds (time 2), this leads to the gradual sharpening and an anterior shift of the entire gap gene expression pattern. (B) A transcriptional circuit comprising four pd-TFs (Nkx2.2, Olig2, Irx3 and Pax6) linked by a series of cross-repressions determines the response of these genes to Shh-Gli signaling and positions the two progenitor domain boundaries that they define. A mathematical model of the circuit recapitulates the pattern and temporal sequence of gene expression observed in neural progenitors: Olig2 expression is induced in ventral neural progenitors before Nkx2.2; Nkx2.2 induction represses Olig2, resulting in an overall dorsal shift in pattern in vivo. A phase portrait based on the mathematical model illustrates the connections between the levels or durations of signal. Compared with Olig2, the induction of Nkx2.2 requires higher levels and longer durations of Shh-Gli activity. The dynamics of Shh signaling at three different positions in the neural tube are indicated with dotted purple lines. The portrait also illustrates that transient high levels of signaling at early times (purple dashed line) are not sufficient to switch from Olig2 to Nkx2.2, provided that this level of signaling is not sustained. (C) The transcriptional circuit produces hysteresis. Nkx2.2 induction by Shh-Gli signaling requires the repression of Pax6 and Olig2; this necessitates high levels of Gli activity (bottom green line). Once induced, Nkx2.2 inhibits Pax6 and Olig2 expression, thereby allowing Nkx2.2 expression to be sustained at lower levels of Shh-Gli signaling (top green line). This might explain how gene expression is maintained as Shh-Gli activity decreases below inducing levels.

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