Retinoid receptors in vertebrate limb development.

Although the precise role of retinoids in limb development remains obscure, the finding that retinoic acid can produce major alterations in limb patterning suggests that this ligand might be involved in the process of limb morphogenesis. Here we describe the patterns of expression of retinoic acid receptors and cytosolic retinoid binding proteins during the course of limb morphogenesis. Examining the distribution of these molecules in the limb and correlating their presence with important processes in limb development could help elucidate their possible functions.     

Morphogen gradients,in theory

The idea that morphogen gradients are established by a process of repeated cycles of exocytosis and endocytosis-so-called planar transcytosis-has been gaining acceptance. This is now challenged by a theoretical approach that experimental biologists should not dismiss; diffusive mechanisms of gradient formation may be correct after all.     

Morphogen gradients: new insights from DPP.

The Drosophila TGFbeta family member Decapentaplegic (DPP) has been proposed to function as a morphogen to pattern cell fields in a number of developmental contexts. A series of recent reports add significantly to our knowledge of the mechanisms of DPP-gradient formation and interpretation. These reports identity additional genes and genetic circuitry necessary for this patterning system, and they highlight variations that might reflect developmental constraints within individual target cell fields.     

Morphogen gradients: expand and repress

An expansion-repression mechanism by which morphogen gradients can adjust to size and growth had been postulated as a model. Now, its molecular nature has been uncovered.     

Muscle development during vertebrate limb outgrowth

Limb development has become one of the model systems for studying vertebrate development. One crucial aspect in limb development is the origin, differentiation and patterning of muscle. Much progress has been made in recent years towards understanding this process. One of the general observations is that the genes involved in limb muscle development appear to be very similar to those involved in muscle development in other regions of the embryo. In this review, we summarize some of the genes and mechanisms that regulate limb muscle development and discuss various avenues along which a deeper understanding can be gained of how muscle cells originate and differentiate in different tissues during vertebrate development.     

Morphogen gradients: nodal enters the stage

Morphogen gradients are proposed to organise cell fates during development via the long-range activity of secreted molecules. Their existence in vertebrates, however, has been debated. A recent study has identified the Nodal-related protein Squint as a bona fide morphogen in vertebrate mesoderm.     

Morphogen to mitogen: the multiple roles of hedgehog signalling in vertebrate neural development

Sonic hedgehog has received an enormous amount of attention since its role as a morphogen that directs ventral patterning in the spinal cord was discovered a decade ago. Since that time, a bewildering array of information has been generated concerning both the components of the hedgehog signalling pathway and the remarkable number of contexts in which it functions. Nowhere is this more evident than in the nervous system, where hedgehog signalling has been implicated in events as disparate as axonal guidance and stem cell maintenance. Here we review our present knowledge of the hedgehog signalling pathway and speculate about areas in which further insights into this versatile pathway might be forthcoming.     

Achieving bilateral symmetry during vertebrate limb development

While the various internal organs of vertebrates display many obvious left–right asymmetries in their location and/or morphology, external features exhibit a high degree of bilateral symmetry. How this external bilateral symmetry is established during development is largely unknown. In this review, we explore several mechanisms, in place during development, that regulate the final size of the limb. These mechanisms rely on the presence of positive signaling feedback loops during limb bud growth. Through the activity of these signaling loops and their eventual breakdown when the limb bud has reached a certain size, bilateral symmetry can be achieved.     

Patterning in the vertebrate limb.

The past few years have seen the isolation and characterization of some of the genes involved in the control of limb pattern formation. Their possible role in this fundamental process is discussed in the light of recent data, and an attempt is made to superimpose this molecular approach to patterning on pre-existing conceptual views.     

Recent progress in vertebrate limb morphogenesis.

Morphogenesis of vertebrate limb, specifically that of the chick wing, has been recognized as a suitable model to study the cellular and molecular mechanisms of pattern formation. The importance of cellular inductive phenomena and the relevance of the processes such as cell division and cell death in the above model are discussed. These studies have revealed the retinoic acid (RA) and retinols as convincing candidates for vertebrate morphogens. The recent discovery that the RA receptors belong to the steroid hormone receptor superfamily might indicate the universality of the RA morphogen and might enlighten the possible mode of its action. Identification and characterization of the 1d locus genes associated with the mouse limb morphogenesis and the possible involvement of the homeobox proteins in chick wing development have opened new prospects in understanding the molecular mechanisms of vertebrate morphogenesis.     

The role of Hox genes during vertebrate limb development

The potential role of Hox genes during vertebrate limb development was brought into focus by gene expression analyses in mice (P Dolle, JC Izpisua-Belmonte, H Falkenstein, A Renucci, D Duboule, Nature 1989, 342:767-772), at a time when limb growth and patterning were thought to depend upon two distinct and rather independent systems of coordinates; one for the anterior-to-posterior axis and the other for the proximal-to-distal axis (see D Duboule, P Dolle, EMBO J 1989, 8:1497-1505). Over the past years, the function and regulation of these genes have been addressed using both gain-of-function and loss-of-function approaches in chick and mice. The use of multiple mutations either in cis-configuration in trans-configuration or in cis/trans configurations, has confirmed that Hox genes are essential for proper limb development, where they participate in both the growth and organization of the structures. Even though their molecular mechanisms of action remain somewhat elusive, the results of these extensive genetic analyses confirm that, during the development of the limbs, the various axes cannot be considered in isolation from each other and that a more holistic view of limb development should prevail over a simple cartesian, chess grid-like approach of these complex structures. With this in mind, the functional input of Hox genes during limb growth and development can now be re-assessed.     

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.     

Morphogen pattern formation and development in growth

The dependence of the spatial concentration profiles of morphogens on a characteristic dimension is obtained by continuation techniques for Gierer and Meinhardt's activator-inhibitor model of morphogenesis. The study of the behaviour of the system during growth, where the linear and exponential increase of the characteristic dimension is considered, revealed that more complex patterns of morphogen spatial concentrations appear regularly in a reproducible way.     

Interplay between the molecular signals that control vertebrate limb development

Vertebrate limbs display three obvious axes of asymmetry. These three axes are referred to as proximal-distal (Pr-D; shoulder to digit tips), anterior-posterior (A-P; thumb to little finger), and dorsal-ventral (D-V; back of hand to palm). At a molecular level, it is now possible to define the signals that control patterning of each of the three axes of the developing limb. These signals do not work in isolation though but rather their activity must be integrated such that the various limb elements are coordinately formed with relation to these three axes. This review will provide an overview of the intricate medley amongst the molecular signals that serve to establish and coordinate patterning information along the three primary axes of the limb.     

The growth and form development of the limb buds in vertebrate animals

The development of the fin and limb buds involves a balance of centrifugal (active) and centripetal (passive) mechanical forces, the first of which acts to move the walls of these structures away from each other and the second holds them together. When the volume of the mesodermal core increases, the generated force meets with the resistance of the basal membrane, and as a result, the limb bud has a tendency to acquire cylindrical shape. Collagen fibers, individual mesenchymal cells, and their groups hold together the dorsal and the ventral wall of the limb bud, prevent the movement of these walls away from each other, and in this way direct bud growth along the proximodistal and the anteroposterior axes. The balance of the forces, which stretch the ectodermal layer, and those, which constrain it, have also been observed in the development of other body parts.