d eve stripe 2 element
-1550 Kr5 gt3 gt2 Kr4
gt1 Kr3 -1070
Regulation of a pair-rule stripe: combinatorial control of an independent c/s-regulatory element
The regulation of the even-skipped c/s-regulatory element controls the formation of the second stripe in the early embryo. (a) The stripe 2 element controls just one of seven stripes of eve expression. (b) The stripe forms within the domain of the Bicoid and Hunchback proteins and at the edge of the Giant and Krüppel gap protein domains. The former are activators, and the latter are repressors, of eve stripe 2 expression. (c) The eve stripe 2 element spans from about 1.7 to 1.0 kilobases upstream of the eve transcription unit. (d) Within this element, several binding sites for each regulator exist. The net output of the combination of activators and repressors is expression of the narrow eve stripe.
Source: Modified from Gerhart J, Kirschner M. Cells, embryos and evolution. Cambridge, MA: Blackwell Science, 1997.
The regulation of segment polarity gene expression in Drosophila segments
The maintenance of segment polarity gene expression in specific domains within each segment is controled by signaling interactions between cells. (top) Embryo double-labeled to reveal wingless (black) and engrailed (brown) expression in stripes of adjacent cells in each segment. (bottom) Hedgehog signaling from Engrailed-expressing cells (right) to cells anterior (left) induces wingless expression through the members of the Hedgehog pathway (Patched/Smoothened/Costal/Fused/Ci). Wingless, in turn, signals back to posterior cells through components of the Wingless pathway (Frizzled/DFrizzled2/Dsh/Zw3/Arm/TCF) to maintain engrailed expression. Source: Figure parts courtesy of Roel Nusse and Nipam Patel.
through the Ptc receptor and several transducers (Fig. 3.8), to activate wingless expression in adjacent anterior cells. Wg, in turn, signals back to posterior cells through the Wingless receptor complex (D-fz and Arrow) and various signal transducers (see Table 2.2), to maintain engrailed expression, Hh expression, and the continuity of the regulatory circuit (Fig. 3.8). Signaling between cell populations to initiate and maintain gene expression patterns is a general feature of cellular fields. Indeed, these signaling molecules play a wide variety of roles in animal development.
General lessons from the segmentation genes
The A/P segmentation hierarchy illustrates five general concepts concerning the spatial regulation of gene expression in animal development:
1. The concentration-dependent response of genes to graded inputs is illustrated by the regulation of gap target genes by the Bicoid protein. Both threshold and graded responses to inducers are major themes of gene regulation in cellular fields as well.
2. The action of both activators and repressors determines all of the gap and many of the pair-rule and segment polarity gene expression patterns. The refinement of gene expression patterns from those covering most of the embryo (maternal proteins), to 15-to 20-cell-wide regions (gap proteins), to 3- to 4-cell-wide stripes (pair-rule proteins), and ultimately to 1- to 2-cell-wide stripes (segment polarity proteins), depends on activators that define potential areas of gene activation and repressors that restrict the areas in which target genes are expressed. The spatial repression of gene expression to carve ever-finer patterns out of larger domains is a major regulatory theme in cellular fields.
3. Many genes are regulated by two or more activators or repressors. Combinatorial regulation imposes greater specificity and allows for a greater diversity of spatial patterns.
4. Multiple independent cis-regulatory elements regulate the expression of many segment genes. Individual elements control individual domains of gene expression (for example, each pair-rule stripe). Furthermore, many segmentation genes are also expressed in the developing nervous system in unique patterns that are controlled by other discrete cis-regulatory elements. The utilization of multiple independent elements controlling different spatial domains of gene expression is a general theme of developmental gene regulation.
5. The sequential activation of gap, pair-rule, and segment polarity genes, with each tier of genes being dependent on the preceding tier, constitutes a regulatory hierarchy. The domino-like activation of genes in sequence assures the proper temporal deployment of developmental genes.
Like the A/P axis, the dorsoventral (D/V) axis of the Drosophila embryo is subdivided into a series of domains that give rise to different tissues. Ventral-most cells will form mesoderm, more ventrolateral cells will give rise to the neuroectoderm, lateral regions generate the dorsal epidermis, and dorsal cells produce an extraembryonic structure, the amnioserosa (Fig. 3.9a). Although subdivision of the D/V axis is accomplished by an entirely different set of genes from those that regulate the A/P axis, both transformations occur through similar transcriptional regulatory mechanisms. Combinations of activators and repressors, including some that work in a concentration-dependent manner, act on discrete cis-regulatory elements to carve out the spatial boundaries of downstream pattern-regulating genes.
A maternal transcription factor gradient also organizes the D/V axis. This gradient is established by regulating the nuclear localization of the Dorsal (Dl) protein. The highest concentrations of the nuclear Dorsal protein are found in ventral cells, lower levels occur in ventrolateral and lateral regions, and no nuclear Dorsal protein is found in dorsal-most regions (Fig. 3.9c). The protein is required in the ventral region to induce ventral tissues.
More than 40 zygotic genes are regulated by different threshold responses to Dorsal protein concentration along the D/V axis, a few of which have been examined in great detail (Fig. 3.9b). The response of genes to the Dorsal gradient depends on the number and affinity of binding sites for the Dorsal protein within the cis-regulatory elements of target genes. Low-affinity sites are occupied only at high concentrations of Dl nuclear protein, which are found in ventral-most cells. For example, the twist and snail response elements contain low-affinity sites and are activated in ventral-most cells. By contrast, high-affinity sites can be occupied at low concentrations of Dorsal. The rhomboid gene cis-element, for example, contains high-affinity sites and is activated by lower concentrations of Dorsal in lateral regions. This protein also acts as a repressor to prevent the expression of genes such as zen and dpp in ventral and lateral regions of the embryo.
Mesoderm tolliod dpp zen tolliod dpp zen
rhomboid twist snail
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