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L Wolpert

Publications and source records attributed to L Wolpert.

At least 37 records · Page 2Linked to original sources
PubMed1998

Pattern formation in epithelial development: the vertebrate limb and feather bud spacing.

The ectoderm of the vertebrate limb and feather bud are epithelia that provide good models for epithelial patterning in vertebrate development. At the tip of chick and mouse limb buds is a thickening, the apical ectodermal ridge, which is essential for limb bud outgrowth. The signal from the ridge to the underlying mesoderm involves fibroblast growth factors. The non-ridge ectoderm specifies the dorsoventral pattern of the bud and Wnt7a is a dorsalizing signal. The development of the ridge involves an interaction between dorsal cells that express radical fringe and those that do not. There are striking similarities between the signals and genes involved in patterning the limb ectoderm and the epithelia of the Drosophila imaginal disc that gives rise to the wing. The spacing of feather buds involves signals from the epidermis to the underlying mesenchyme, which again include Wnt7a and fibroblast growth factors.

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PubMed1998

Local inhibitory action of BMPs and their relationships with activators in feather formation: implications for periodic patterning.

The formation of periodic patterns is fundamental in biology. Theoretical models describing these phenomena have been proposed for feather patterning; however, no molecular candidates have been identified. Here we show that the feather tract is initiated by a continuous stripe of Shh, Fgf-4, and Ptc expression in the epithelium, which then segregates into discrete feather primordia that are more strongly Shh and Fgf-4 positive. The primordia also become Bmp-2 and Bmp-4 positive. Bead-mediated delivery of BMPs inhibits local feather formation in contrast with the activators, SHH and FGF-4, which induce feather formation. Both FGF-4 and SHH induce local expression of Bmp-4, while BMP-4 suppresses local expression of both. FGF-4 also induces Shh. Based on these findings, we propose a model that involves (1) homogeneously distributed global activators that define the field, (2) a position-dependent activator of competence that propagates across the field, and (3) local activators and inhibitors triggered in sites of individual primordia that act in a reaction-diffusion mechanism. A computer simulation model for feather pattern formation is also presented.

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PubMed1998

Mechanisms for positional signalling by morphogen transport: a theoretical study.

Gradients of cellular activities are ubiquitous in embryonic development. It is widely believed that the inhomogeneous spatial distribution of a morphogen would be able to set up such gradients. But how then does the morphogen propagate in the first place? Straightforward molecular diffusion is often proposed as a possible mechanism. We first show that, surprisingly, the mere binding of the diffusing morphogen to its membrane receptors suffices to prevent the establishment of a concentration-based positional signalling system. Instead, a flat, saturated distribution of receptor-bound morphogen builds up. Because the distribution spreads gradually from the morphogen source, however, cells may still know their position if they are able to integrate the morphogen signal in time. The irregularities of diffusion in the complex extracellular medium would in fact be partially compensated for by such time summation. Another, non-exclusive possibility is that morphogen transport does not occur by simple diffusion only. We put forth a novel model of receptor-aided, directed diffusion that achieves a spatial distribution of morphogen. Our model is based, as an illustration, on the properties of members of the TGFbeta family of molecules. We show that two simple hypotheses regarding the kinetics of TGBbeta binding to its receptors suffice to establish a remarkable transfer mechanism whereby a morphogen such as activin could be both propagated along cell membranes, and transferred between cells that are in contact. The model predicts that morphogen propagation properties depend strongly on the closeness of cell-cell appositions, does not necessitate protein synthesis, accumulation or slow degradation (in contrast to the diffusion/time integration model), and that the morphogen is localised mostly on or close to cell membranes.

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PubMed1998

Debatable issues. Interview by Alain Ghysen..

This paper reports a discussion between Antonio Garcia-Bellido and Lewis Wolpert about a number of questions raised by Alain Ghysen. The questions follow, in reverse order, the subjects dealt with in this issue: first the principles (are there unifying principles of development?), then questions dealing with evolution (why are patterns conserved?) and with the homeotic genes (what is their function?), then the cell biology of development (who is controlling actual morphogenesis?), and the generation and evolution of patterns (what makes development so reproducible and how does it change from one species to another?) and finally about the genetics of cell determination and specification (how does a cell measure its position?). Obviously the discussion did not provide any firm answers to any of these questions. Perhaps more importantly, it provides a vivid picture of two contrasting ways of thinking about developmental problems.

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PubMed1997

Genomes.

Explore the source record for details and available documents.

Animals↗
PubMed1997

Cell fate in the chick limb bud and relationship to gene expression.

We have produced detailed fate maps for mesenchyme and apical ridge of a stage 20 chick wing bud. The fate maps of the mesenchyme show that most of the wing arises from the posterior half of the bud. Subapical mesenchyme gives rise to digits. Cell populations beneath the ridge in the mid apical region fan out into the anterior tip of the handplate, while posterior cell populations extend right along the posterior margin. Subapical mesenchyme of the leg bud behaves similarly. The absence of anterior bending of posterior cell populations has implications when considering models of vertebrate limb evolution. The fatemaps of the apical ridge show that there is also a marked anterior expansion and cells that were in anterior apical ridge later become incorporated into non-ridge ectoderm along the margin of the bud. Mesenchyme and apical ridge do not expand in concert--the apical ridge extends more anteriorly. We used the fatemaps to investigate the relationship between cell lineage and elaboration of Hoxd-13 and Fgf-4 domains. Hoxd-13 and Fgf-4 are initially expressed posteriorly until about the mid-point of the early wing bud in mesenchyme and apical ridge respectively. Later in development, the genes come to be expressed throughout most of the handplate and apical ridge respectively. We found that at the proximal edge of the Hoxd-13 domain, cell populations stopped expressing the gene as development proceeded and found no evidence that the changes in extent of the domains were due to initiation of gene expression in anterior cells. Instead the changes in extent of expression fit with the fate maps and can be attributed to expansion and fanning out of cell populations initially expressing the genes.

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PubMed1996

Overexpression of BMP-2 and BMP-4 alters the size and shape of developing skeletal elements in the chick limb.

Bone morphogenetic proteins are members of the transforming growth factor beta (TGF beta) superfamily which are involved in a range of developmental processes including modelling of the skeleton. We show here that Bmp-2 is expressed in mesenchyme surrounding early cartilage condensations in the developing chick limb, and that Bmp-4 is expressed in the perichondrium of developing cartilage elements. To investigate their roles during cartilage development, BMP-2 and BMP-4 were expressed ectopically in developing chick limbs using retroviral vectors. Over-expression of BMP-2 or BMP-4 led to a dramatic increase in the volume of cartilage elements, altered their shapes and led to joint fusions. This increase in volume appeared to result from an increase in the amount of matrix and in the number of chondrocytes. The latter did not appear to be due to increased proliferation of chondrocytes, suggesting that it may result from increased recruitment of precursors. BMP-2 and BMP-4 also delayed hypertrophy of chondrocytes and formation of the osteogenic periosteum. These data provide insights into how BMP-2 and BMP-4 may model and control the growth of skeletal elements during normal embryonic development, suggesting roles for both molecules in recruiting non-chondrogenic precursors to chondrogenic fate.

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PubMed1996

One hundred years of positional information.

One mechanism by which spatial patterns of cell differentiation could be specified during embryonic development and regeneration is based on positional information. Cells acquire a positional value with respect to boundaries and then interpret this in terms of a programme determined by their genetic constitution and developmental history. The signals and the molecular basis of such a system have both been rather well conserved. Recent work has shown that cells can respond to quite small differences in the concentrations of molecules whose concentration could provide positional information.

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PubMed1995

Evolution of the cell theory.

The problem of the nature of life has a long history going back to the Greeks. There was little real progress until the 19th century and Aristotle may have been at home with many 18th century ideas about vital forces and basic units. Although Hooke described cells in 1665 it took a further 200 years for the significance and nature of cells to be appreciated. In the mid 18th century some considered the basic building blocks of living matter to be fibrous. Globular theories, the precursor to the cell theory, were quite popular at the beginning of the 19th century. Many workers, as microscopes improved, had described various cell types and structures including the nucleus but the idea that cells were the universal units is associated with in 1838 and that of Schwann in 1839. However, Schwann mistakenly thought that cells could form de novo. Cell division was established by Remak and others in the 1850s. Mitosis was first understood by Flemming in 1882. The existence of the animal cell membrane was only established by the beautiful experiments of Overton in 1895. The history of the cell theory can be used to show that progress can be based on incorrect but productive ideas. It is one of the most important ideas in all of biology.

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PubMed1995

Gene expression, polarising activity and skeletal patterning in reaggregated hind limb mesenchyme.

The developing chick limb has two major signalling centres; the apical ectodermal ridge maintains expression of several important genes and outgrowth of the limb, and the polarising region specifies the pattern of skeletal elements along the anteroposterior axis. We have used reaggregated leg grafts (mesenchyme dissociated into single cells, placed in an ectodermal jacket and grafted to a host) to study patterning in a system where the developmental axes are severely disrupted. Reaggregates from different regions of leg mesenchyme developed correspondingly different digits, giving a system in which skeletal phenotype could be compared with the expression of genes thought to be important in patterning. We found that posterior third and whole leg reaggregates gave rise to different digits, yet expressed the same combination of HoxD, Bmp-2 and shh genes throughout their development. Anterior thirds initially only express the 3' end of the HoxD cluster but activate the more 5' members of the cluster sequentially over a period of 48 hours, a period during which Bmp-2 is activated but no shh or Fgf-4 expression could be detected. Our results suggest that there are two independent mechanisms for activating the HoxD complex, one polarising region-dependent and one independent, and that shh expression may not be necessary to maintain outgrowth and patterning once a ridge has been established.

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PubMed1994

Positional information and pattern formation in development.

A widely used mechanism for pattern formation is based on positional information: cells acquire positional identities as in a coordinate system and then interpret this information according to their genetic constitution and developmental history. In Drosophila maternal factors establish the axes and set up a maternal system of positional information on which further patterning is built. There is a cascade of gene activity which leads both to the development of periodic structures, the segments, and to their acquiring a unique identity. This involves the binding of transcription factors to regulatory regions of genes to produce sharp thresholds. Many of the genes involved in these processes, particularly the Hox complex, are also involved in specifying the body axis and limbs of vertebrates. There are striking similarities in the mechanisms for specifying and recording positional identity in Drosophila and vertebrates.

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PubMed1994

The evolutionary origin of development: cycles, patterning, privilege and continuity.

A scenario for the evolution of a simple spherical multicellular organism from a single eukaryotic cell is proposed. Its evolution is based on environmentally induced alterations in the cell cycle, which then, by the Baldwin effect, become autonomous. Further patterning of this primitive organism--a Blastaea, could again involve environmentally induced signals like contact with the substratum, which could then become autonomous, by, perhaps, cytoplasmic localization and asymmetric cell division. Generating differences between cells based on positional information is probably very primitive, and is well conserved; its relation to asymmetric cell division is still unclear. Differentiation of new cell types can arise from non equivalence and gene duplication. Periodicity also evolved very early on. The origin of gastrulation may be related to mechanisms of feeding. The embryo may be evolutionarily privileged and this may facilitate the evolution of novel forms. Larvae are secondarily derived and direct development is the primitive condition as required by the continuity principle.

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