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Controlling embryonic growth Most animal embryos grow through cell accumulation in a posterior growth zone, but the morphogenic forces that control the formation and directionality of the growth are unknown. Based on a study of axis elongation during formation of the trunk and tail structures in the chicken embryo, Bénazéraf et al . propose that tissue elongation in response to signalling mediated by fibroblast growth factor is a property emerging from the collective regulation of graded, random cell motion rather than by the regulation of directionality of individual cellular movements. Most animal embryos grow through cell accumulation in a posterior growth zone, but the underlying forces are unknown. It is now proposed that posterior elongation in chicken embryos is an emergent property that arises from graded cell motility in random directions (as opposed to directed movement). This occurs in response to signalling through the fibroblast growth factor. Vertebrate embryos are characterized by an elongated antero-posterior (AP) body axis, which forms by progressive cell deposition from a posterior growth zone in the embryo. Here, we used tissue ablation in the chicken embryo to demonstrate that the caudal presomitic mesoderm (PSM) has a key role in axis elongation. Using time-lapse microscopy, we analysed the movements of fluorescently labelled cells in the PSM during embryo elongation, which revealed a clear posterior-to-anterior gradient of cell motility and directionality in the PSM. We tracked the movement of the PSM extracellular matrix in parallel with the labelled cells and subtracted the extracellular matrix movement from the global motion of cells. After subtraction, cell motility remained graded but lacked directionality, indicating that the posterior cell movements associated with axis elongation in the PSM are not intrinsic but reflect tissue deformation. The gradient of cell motion along the PSM parallels the fibroblast growth factor (FGF)/mitogen-activated protein kinase (MAPK) gradient 1 , which has been implicated in the control of cell motility in this tissue 2 . Both FGF signalling gain- and loss-of-function experiments lead to disruption of the motility gradient and a slowing down of axis elongation. Furthermore, embryos treated with cell movement inhibitors (blebbistatin or RhoK inhibitor), but not cell cycle inhibitors, show a slower axis elongation rate. We propose that the gradient of random cell motility downstream of FGF signalling in the PSM controls posterior elongation in the amniote embryo. Our data indicate that tissue elongation is an emergent property that arises from the collective regulation of graded, random cell motion rather than by the regulation of directionality of individual cellular movements.

The dorsal-ventral patterning of the Drosophila embryo is controlled by Dorsal, a sequence-specific transcription factor that is related to mammalian NF-[kappa]B. Previous chromatin immunoprecipitation-chip assays predicted that as many as a third or even half of all Dorsal target genes contain multiple enhancers for the same or similar expression pattern. We show that some of these secondary enhancers, or \"shadow enhancers,\" produce gene expression patterns that overlap those produced by the primary enhancers in transgenic embryos. We suggest that shadow enhancers help ensure the precision of embryonic patterning and discuss their importance in the evolution of genetic novelty. [PUBLICATION ABSTRACT]

Only mammals have relinquished parthenogenesis, a means of producing descendants solely from maternal germ cells. Mouse parthenogenetic embryos die by day 10 of gestation 1 , 2 , 3 , 4 . Bi-parental reproduction is necessary because of parent-specific epigenetic modification of the genome during gametogenesis 5 , 6 , 7 , 8 . This leads to unequal expression of imprinted genes from the maternal and paternal alleles 9 . However, there is no direct evidence that genomic imprinting is the only barrier to parthenogenetic development. Here we show the development of a viable parthenogenetic mouse individual from a reconstructed oocyte containing two haploid sets of maternal genome, derived from non-growing and fully grown oocytes. This development was made possible by the appropriate expression of the Igf2 and H19 genes with other imprinted genes, using mutant mice with a 13-kilobase deletion in the H19 gene 10 as non-growing oocytes donors. This full-term development is associated with a marked reduction in aberrantly expressed genes. The parthenote developed to adulthood with the ability to reproduce offspring. These results suggest that paternal imprinting prevents parthenogenesis, ensuring that the paternal contribution is obligatory for the descendant.

The identities of the digits of the avian forelimb are disputed. Whereas paleontological findings support the position that the digits correspond to digits one, two, and three, embryological evidence points to digit two, three, and four identities. By using transplantation and cell-labeling experiments, we found that the posteriormost digit in the wing does not correspond to digit four in the hindlimb; its progenitor segregates early from the zone of polarizing activity, placing it in the domain of digit three specification. We suggest that an avian-specific shift uncouples the digit anlagen from the molecular mechanisms that pattern them, resulting in the imposition of digit one, two, and three identities on the second, third, and fourth anlagens.

To determine the role of fibroblast growth factor (FGF) signalling from the apical ectodermal ridge (AER), we inactivated Fgf4 and Fgf8 in AER cells or their precursors at different stages of mouse limb development. We show that FGF4 and FGF8 regulate cell number in the nascent limb bud and are required for survival of cells located far from the AER. On the basis of the skeletal phenotypes observed, we conclude that these functions are essential to ensure that sufficient progenitor cells are available to form the normal complement of skeletal elements, and perhaps other limb tissues. In the complete absence of both FGF4 and FGF8 activities, limb development fails. We present a model to explain how the mutant phenotypes arise from FGF-mediated effects on limb bud size and cell survival.

Regulating the nuclear factor-κB (NF-κB) family of transcription factors is of critical importance to animals, with consequences of misregulation that include cancer, chronic inflammatory diseases and developmental defects 1 . Studies in Drosophila melanogaster have proved fruitful in determining the signals used to control NF-κB proteins, beginning with the discovery that the Toll/NF-κB pathway, in addition to patterning the dorsal–ventral axis of the fly embryo, defines a major component of the innate immune response in both Drosophila and mammals 2 , 3 . Here, we characterize the Drosophila wntD (Wnt inhibitor of Dorsal) gene. We show that WntD acts as a feedback inhibitor of the NF-κB homologue Dorsal during both embryonic patterning and the innate immune response to infection. wntD expression is under the control of Toll/Dorsal signalling, and increased levels of WntD block Dorsal nuclear accumulation, even in the absence of the IκB homologue Cactus. The WntD signal is independent of the common Wnt signalling component Armadillo (β-catenin). By engineering a gene knockout, we show that wntD loss-of-function mutants have immune defects and exhibit increased levels of Toll/Dorsal signalling. Furthermore, the wntD mutant phenotype is suppressed by loss of zygotic dorsal . These results describe the first secreted feedback antagonist of Toll signalling, and demonstrate a novel Wnt activity in the fly.

Although previous analyses indicate that neocortical neurons originate from the cortical proliferative zone, evidence suggests that a subpopulation of neocortical interneurons originates within the subcortical telencephalon. For example, γ-aminobutyric acid (GABA)-expressing cells migrate in vitro from the subcortical telencephalon into the neocortex. The number of GABA-expressing cells in neocortical slices is reduced by separating the neocortex from the subcortical telencephalon. Finally, mice lacking the homeodomain proteins DLX-1 and DLX-2 show no detectable cell migration from the subcortical telencephalon to the neocortex and also have few GABA-expressing cells in the neocortex.

The ‘progress zone’ model provides a framework for understanding progressive development of the vertebrate limb 1 . This model holds that undifferentiated cells in a zone of fixed size at the distal tip of the limb bud (the progress zone) undergo a progressive change in positional information such that their specification is altered from more proximal to more distal fates. This positional change is thought to be driven by an internal clock that is kept active as long as the cells remain in the progress zone. However, owing to cell division, the most proximal of these cells are continually pushed outside the confines of the zone. As they exit, clock function ceases and cells become fixed with the positional value last attained while within the zone. In contrast to this model, our data suggest that the various limb segments are ‘specified’ early in limb development as distinct domains, with subsequent development involving expansion of these progenitor populations before differentiation. We also find, however, that the distal limb mesenchyme becomes progressively ‘determined’, that is, irreversibly fixed, to a progressively limited range of potential proximodistal fates.

Embryological and genetic evidence indicates that the vertebrate head is induced by a different set of signals from those that organize trunk–tail development 1 , 2 , 3 , 4 , 5 , 6 . The gene cerberus encodes a secreted protein that is expressed in anterior endoderm and has the unique property of inducing ectopic heads in the absence of trunk structures 1 . Here we show that the cerberus protein functions as a multivalent growth-factor antagonist in the extracellular space: it binds to Nodal, BMP and Wnt proteins via independent sites. The expression of cerberus during gastrulation is activated by earlier nodal-related signals in endoderm and by Spemann-organizer factors that repress signalling by BMP and Wnt. In order for the head territory to form, we propose that signals involved in trunk development, such as those involving BMP, Wnt and Nodal proteins, must be inhibited in rostral regions.

Knowing when and where a given protein is activated within intact animals assists in elucidating its in vivo function. With the use of a genetically encoded A-probe (activation bioprobe), we revealed that Cdc42 guanosine triphosphatase (GTPase) remains inactive within Drosophila embryos during the first two-thirds of embryogenesis. Within the central nervous system where Cdc42 activity first becomes up-regulated, individual neurons display patterns restricted to specific subcellular compartments. At both organismal and cellular levels, Cdc42's endogenous activation patterns in the wild type allow predictions of where loss-of-function phenotypes will emerge in cdc42/cdc42 mutants. Genetic tests support the importance of suppressing endogenous Cdc42 activities until needed. Thus, bioprobe-assisted analysis uncovers how ubiquitously expressed signaling proteins control cellular events through continual regulation of their activities within animals.