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• W2016114514 abstract "“Preformation is represented by DNA, not by … a tiny adult in every sperm …”—Antonio García-Bellido (1998)“The key to understanding how genomic regulatory networks … work lies in experimental analysis of cis-regulatory systems at all levels of the regulatory network.”—1Arnone M.I Davidson E.H Development. 1997; 124: 1851-1864PubMed Google Scholar The analysis of developmental control mechanisms has for many years been dominated by Entwicklungsmechanik (“experimental embryology”), a discipline whose principal premise is to uncover biological constraints by studying the behavior of embryonic cells when placed in conditions other than their normal environment. The best experiments designed along these principles can disclose epigenetic signals and responses, such as induction, which govern changes in the direction of cell differentiation. It has been known since the 1920s that signals from a special region, the “organizer,” can divert the fate of prospective skin to nervous system, and that the induced nervous system is perfectly patterned along its head-to-tail (anterior–posterior) axis. Three models were proposed to account for this. The first, advanced by 11Mangold O Naturwissenschaften. 1933; 21: 761-766Crossref Scopus (171) Google Scholar, suggested that distinct organizer activities are responsible for inducing the head, trunk, and tail of the embryo. In support for this, organizers from donor embryos older than gastrula stage induce a nervous system lacking anterior brain regions (10Knezevic V DeSanto R Mackem S Development. 1998; 125: 1791-1801PubMed Google Scholar, and references therein). A second model (18Waddington C.H Needham J Proc. Kon. Akad. Wetensch. Amsterdam. 1936; 39: 887-891Google Scholar) proposes that initial signals from the organizer (“evocation”) produce a nervous system without any regional character and that its pattern is conferred by later signals (“individuation”). Indeed, it is possible to generate a neural plate that expresses general neural markers, but no region-specific markers (17Streit A Sockanathan S Perez L Rex M Scotting P.J Sharpe P.T Lovell-Badge R Stern C.D Development. 1997; 124: 1191-1202PubMed Google Scholar). Finally, 15Nieuwkoop P.D Nigtevecht G.V J. Embryol. Exp. Morph. 1954; 2: 175-193Google Scholar suggested that the nervous system generated by initial neuralizing signals (“activation”) is always anterior in character (forebrain), and that subsequent signals can alter (“transform”) the fate of some of these cells, generating posterior nervous system. Consistent with this model, 2Cox W.G Hemmati-Brivanlou A Development. 1995; 121: 4349-4358PubMed Google Scholar showed that a tail portion of the amphibian embryo can cause a head portion (mainly prospective forebrain) to express intermediate (hindbrain) neural markers. Although there is some supporting evidence for each model, these three views are apparently incompatible. How many different signals are involved? At one extreme, Mangold’s model could be interpreted to mean that there are as many distinct signals as there are regions in the nervous system. At the other, Nieuwkoop’s model is consistent with just one, or very few, graded signals, which act quantitatively to impart progressively more posterior character to the nervous system as development proceeds. But embryos seem to be more resourceful than the investigators who study them, and mechanisms other than those implied by these three models can at least refine anteroposterior pattern. For example, the prechordal mesendoderm emits signals that can anteriorize the hindbrain (3Dale J.K Vesque C Lints T.J Sampath T.K Furley A Dodd J Placzek M Cell. 1997; 90: 257-269Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar, 4Foley A.C Storey K.G Stern C.D Development. 1997; 124: 2983-2996PubMed Google Scholar, 16Pera E.M Kessel M Development. 1997; 124: 4153-4162PubMed Google Scholar), and interactions between adjacent regions within the neural tube can regulate the expression of regional markers (e.g., 8Itasaki N Ichijo H Hama L Matsuno T Nakamura H Development. 1991; 113: 1133-1144PubMed Google Scholar, 13Martínez S Wassef M Alvarado-Mallart R.M Neuron. 1991; 6: 971-981Abstract Full Text PDF PubMed Scopus (288) Google Scholar). Despite this richness of ideas and experimental efforts, it seems remarkable that we still don’t know how many signals are required to pattern the nervous system, from where these signals emanate, or how they produce complex patterns of expression of many different markers along the axis. Some of the targets of these signals within the hindbrain and trunk have been discovered. The Hox genes are organized in clusters, such that their arrangement along the chromosome (in the 3′-to-5′ direction) reflects both their most anterior border of expression (3′ being more anterior) and the onset of their expression (3′ being earlier). We also know that these Hox genes can be regulated by retinoids, which control their expression in a time- and concentration-dependent way: higher doses or longer treatments induce progressively more posterior (5′) genes in the cluster (reviewed by 12Marshall H Morrison A Studer M Popperl H Krumlauf R FASEB J. 1996; 10: 969-978Crossref PubMed Scopus (214) Google Scholar). This finding, and the discovery that FGF can mimic tail/trunk mesoderm in inducing more posterior nervous system from prospective forebrain (2Cox W.G Hemmati-Brivanlou A Development. 1995; 121: 4349-4358PubMed Google Scholar, 14Muhr J Jessell T.M Edlund T Neuron. 1997; 19: 487-502Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar) appear to support Nieuwkoop’s model. A recent paper (7Gould A Itasaki N Krumlauf R Neuron. 1998; 21: 39-51Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar) provides a novel approach to the study of neural patterning, combining the ideas of Entwicklungsmechanik with a molecular dissection of the enhancer elements regulating the expression of one of the Hox genes, Hoxb4, in the hindbrain. The authors use the finding that two separate elements direct expression of Hoxb4. An early neural enhancer (early NE) becomes active at 8.25 days and accounts for the fuzzy anterior boundary of endogenous Hoxb4 expression that appears before rhombomeres become distinct (Figure 1). By 9.5 days, when a second element (late NE) is activated, the anterior border of endogenous Hoxb4 expression becomes fixed at its normal boundary, between rhombomeres 6 and 7 (r6/r7). 7Gould A Itasaki N Krumlauf R Neuron. 1998; 21: 39-51Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar use transgenic mouse lines expressing a reporter gene driven by either the early or the late NE to investigate the signals that control Hoxb4 expression. Do the signals that establish the early and late boundaries of expression reside within the neural tube itself, or do they emanate from neighboring structures? Surprisingly, 7Gould A Itasaki N Krumlauf R Neuron. 1998; 21: 39-51Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar obtain a different answer for each enhancer. In hindbrain explants cultured alone, expression driven by the late NE develops even if the explants are dissected from young (8.25 day) embryos. Therefore, signals that drive the late NE are autonomous to the neural tube or have already been received by the 10-somite stage and only require maturation. Indeed, it had already been shown that Hoxb4 protein itself activates this enhancer, providing positive feedback regulation (6Gould A Morrison A Sproat G White R Krumlauf R Genes Dev. 1997; 11: 900-913Crossref PubMed Scopus (225) Google Scholar). By contrast, strong and stable expression from the early NE is seen only when explants are cut from 24-somite stage embryos. Therefore, some character of the hindbrain must change, under the influence of neighboring structures, at some time before the 24-somite stage. From where do these signals emanate? The early NE does drive expression in long-term culture of hindbrain explants cut from embryos as young as the 6–7 somite stage, provided that neighboring somite tissue is included, suggesting that somite-derived signals can activate this enhancer (see also 9Itasaki N Sharpe J Morrison A Krumlauf R Neuron. 1996; 16: 487-500Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar). Can these signals specify regional identity? The early NE can be induced by somites in more anterior hindbrain, which does not normally express Hoxb4, showing that the somite signal is “instructive.” However, more posterior somites can also activate the early NE in its normal territory, and they are even more potent than somites normally adjacent to this region. These experiments suggest that somites from different levels of the axis do not emit distinct instructive signals, but rather that there is a graded activity within the somite mesoderm (increasing towards the tail of the embryo), which is required for expression from the early NE enhancer (Figure 1). These properties are reminiscent of the “transforming principle” suggested by Nieuwkoop. What is the molecular nature of the somite-derived signals? Retinoids can posteriorize the neural tube by ectopic activation of Hox genes (see above and 12Marshall H Morrison A Studer M Popperl H Krumlauf R FASEB J. 1996; 10: 969-978Crossref PubMed Scopus (214) Google Scholar). 7Gould A Itasaki N Krumlauf R Neuron. 1998; 21: 39-51Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar provide evidence implicating retinoid synthesis in the somite-derived signal or the responses to it (Figure 1). First, retinoic acid can induce the early NE ectopically in vivo when applied to a more anterior region of the hindbrain, and second, disulphiram (an inhibitor of retinoid synthesis) abolishes the induction of the early NE by somites in culture. Retinoids can also act directly on the neural tube: the early NE contains a retinoic acid response element (RARE); point mutations in this element abolish all sites of expression, and replacement of this RARE by that of a more anteriorly expressed Hox gene (Hoxb1) shifts the expression boundary anteriorly. Using an heroic approach, they show that retinoic acid signaling is required in vivo for correct early expression of Hoxb4: early electroporation of a dominant-negative retinoid receptor into the neural tube of intact chick embryos abolishes Hoxb4 expression, but late electroporation (at a time when the late NE should be active) does not. These experiments clearly implicate retinoid signaling as necessary for the induction, but not for maintenance, of Hoxb4 expression in the neural tube both in vivo and in vitro. The authors argue that the somite signal may not itself be retinoic acid, because filters that should allow retinoic acid to pass through diminish induction of the early NE by somites in culture, opening the possibility that the signal is a protein that activates the retinoid pathway within the responding neural tube. However, these experiments still leave open the possibilility that the somite signal may be a retinoid, if this requires a protein chaperone secreted by the somite, or if the retinoid must be released very close to the neural tube by cell processes that cannot pass through the filter. What do we learn from these experiments? At first glance, they do appear to provide considerable direct support for Nieuwkoop’s “activation/transformation” model of nervous system patterning. Somites produce a signal, increasing in strength toward the tail of the embryo, and which is required for expression of Hoxb4 driven by the early NE both in its normal domain and in more anterior regions of the hindbrain. But this paper also tells us that there is much more complexity in the system of signals and responses that pattern the nervous system than the three classical models lead us to expect. It provides a clear experimental demonstration, using a combination of transgenic mouse lines with experimental embryology in chick and mouse embryos, that separate mechanisms exist to induce and maintain the expression of one specific gene that specifies positional address within the hindbrain. However, many of the important questions remain. For example, do the explants that do not express Hoxb4 have a more anterior character, none at all, or do they encode conflicting positional information? What mechanisms pattern the regions of the brain anterior to the hindbrain, where Hox genes are not expressed? If signals are graded, what mechanisms generate the sharp boundaries between rhombomeres and adjacent domains of gene expression? There are only 13 paralogous Hox gene groups, but many more functionally distinct regions within the length of the nervous system; where is the remaining information encoded, and what are the signals for this? As this paper demonstrates, a combination of classical experimental embryology with the dissection of enhancer elements represents a promising new avenue that may help finally to bridge the 300-year-old gap between genetics (“preformation”) and epigenesis." @default.
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• W2016114514 title "Molecular Dissection of Hox Gene Induction and Maintenance in the Hindbrain" @default.
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