Retinoids and vertebrate limb pattern formation

It has long been suggested that pattern formation depends in part on signalling molecules known as 'morphogens', diffusible substances that determine cell fate in a concentration-dependent way. Retinoic acid, a small hydrophobic molecule that binds to nuclear receptors, is a candidate morphogen for specifying the anteroposterior pattern of vertebrate limbs.     

Activator-inhibitor dynamics of vertebrate limb pattern formation

The development of the vertebrate limb depends on an interplay of cellular differentiation, pattern formation, and tissue morphogenesis on multiple spatial and temporal scales. While numerous gene products have been described that participate in, and influence, the generation of the limb skeletal pattern, an understanding of the most salient feature of the developing limb--its quasiperiodic arrangement of bones, requires additional organizational principles. We review several such principles, drawing on concepts of physics and chemical dynamics along with molecular genetics and cell biology. First, a "core mechanism" for precartilage mesenchymal condensation is described, based on positive autoregulation of the morphogen transforming growth factor (TGF)-beta, induction of the extracellular matrix (ECM) protein fibronectin, and focal accumulation of cells via haptotaxis. This core mechanism is shown to be part of a local autoactivation-lateral inhibition (LALI) system that ensures that the condensations will be regularly spaced. Next, a "bare-bones" model for limb development is described in which the LALI-core mechanism is placed in a growing geometric framework with predifferentiated "apical," differentiating "active," and irreversibly differentiated "frozen" zones defined by distance from an apical source of a fibroblast growth factor (FGF)-type morphogen. This model is shown to account for classic features of the developing limb, including the proximodistal (PD) emergence over time of increasing numbers of bones. We review earlier and recent work suggesting that the inhibitory component of the LALI system for condensation may not be a diffusible morphogen, and propose an alternative mechanism for lateral inhibition, based on synchronization of oscillations of a Hes mediator of the Notch signaling pathway. Finally, we discuss how viewing development as an interplay between molecular-genetic and dynamic physical processes can provide new insight into the origin of congenital anomalies.     

Lineage and pattern in the developing vertebrate limb

Skeletal development in the vertebrate limb occurs independently of that of associated muscles and nerves. Patterning of muscles and nerves within the vertebrate limb depends on cues provided by the developing skeleton. Recent work suggests that skeletal pattern formation depends on spatially periodic prepatterns of extracellular matrix, the biosynthesis of which may be stimulated by diffusible growth factors. In concert with the regulation of limb bud size and shape by endogenous retinoids and other substances, this mechanism could explain how characteristic limb asymmetries are generated.     

脊椎动物胚胎骨骼肌的生成

肌肉发生的起始和生肌节的形成是胚胎肌肉发育中的两个关键事件。研究表明,肌肉发生的起始有赖于体节周围组织所产生的分泌因子的影响。这些组织包括体轴结构,侧板中胚层及体节正上方的外胚层,代表性的分子有Ｗｎｔｓ家族的一些成员以及Ｓｈｈ和ＢＭＰ－４;而生肌节的形成则首先依赖与分节化相关的基因,如ｄｅｌｔａ,ｈｅｒ１等的正常功能,分节之后也同样需在周围环境的作用之下形成生肌节。两栖类非洲爪蟾的肌肉发生有其特殊性。本文对这一领域中最近的研究进展作一综合介绍。     

Cell adhesiveness and affinity for limb pattern formation

Stage-dependent cell sorting in vitro is an intriguing property that mesenchymal cells of a chick limb bud have. We previously proposed that N-cadherin, a cell adhesion molecule, is involved in the sorting process and is likely to be a component of the mechanism of proximal-distal patterning in the developing limb (Yajima et al., (1999) Dev. Dynam. 216:274-284). Here, we present more direct evidence that N-cadherin is one of the molecules responsible for regulation of stage-dependent cell sorting in vitro. Our results suggest that N-cadherin, which accumulates in the distal region of the chick limb bud as limb development proceeds, is related to the positional identity that gives rise to the different shapes and numbers of cartilaginous elements along the proximal-distal axis. In this article we also give insights into positional identity which is mediated by Hoxgenes and cell surface property during limb development.     

Limb development: an international model for vertebrate pattern formation

Limb development is an excellent model for studying how patterns of differentiated cells and tissues are generated in vertebrate embryos. The cell interactions that mediate patterning have been discovered and, more recently, some of the molecules involved in these interactions have been identified. This has provided a direct link to genetics and thus to genes that cause human congenital limb defects.     

Concerning mechanisms for the zebra pattern formation in the solar radio emission

The nature of the zebra patterns in continuous type-IV solar radio bursts is discussed. The most comprehensively developed models of such patterns involve mechanisms based on the double plasma resonance and plasma wave-whistler interaction. Over the last five years, there have appeared a dozen papers concerning the refinement of the mechanism based on the double plasma resonance, because, in its initial formulation, this mechanism failed to describe many features of the zebra pattern. It is shown that the improved model of this mechanism with a power-law distribution function of hot electrons within the loss cone is inapplicable to the coronal plasma. In recent papers, the formation of the zebra pattern in the course of electromagnetic wave propagation through the solar corona was considered. In the present paper, all these models are estimated comparatively. An analysis of recent theories shows that any types of zebra patterns can form in the course of radio wave propagation in the corona, provided that there are plasma inhomogeneities of different scales on the wave path. The superfine structure of zebra stripes in the form of millisecond spikes with a strict period of ～30 ms can be attributed to the generation of continuous radio emission in the radio source itself, assuming that plasma inhomogeneities are formed by a finite-amplitude wave with the same period.     

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.     

Physical mechanisms for chemotactic pattern formation by bacteria.

This paper formulates a theory for chemotactic pattern formation by the bacteria Escherichia coli in the presence of excreted attractant. In a chemotactically neutral background, through chemoattractant signaling, the bacteria organize into swarm rings and aggregates. The analysis invokes only those physical processes that are both justifiable by known biochemistry and necessary and sufficient for swarm ring migration and aggregate formation. Swarm rings migrate in the absence of an external chemoattractant gradient. The ring motion is caused by the depletion of a substrate that is necessary to produce attractant. Several scaling laws are proposed and are demonstrated to be consistent with experimental data. Aggregate formation corresponds to finite time singularities in which the bacterial density diverges at a point. Instabilities of swarm rings leading to aggregate formation occur via a mechanism similar to aggregate formation itself: when the mass density of the swarm ring exceeds a threshold, the ring collapses cylindrically and then destabilizes into aggregates. This sequence of events is demonstrated both in the theoretical model and in the experiments.     

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.     

Making digit patterns in the vertebrate limb

The vertebrate limb has been a premier model for studying pattern formation - a striking digit pattern is formed in human hands, with a thumb forming at one edge and a little finger at the other. Classic embryological studies in different model organisms combined with new sophisticated techniques that integrate gene-expression patterns and cell behaviour have begun to shed light on the mechanisms that control digit patterning, and stimulate re-evaluation of the current models.     

"Fingering" the vertebrate limb

A detailed and precise picture is being pieced together about how the pattern of digits develops in vertebrate limbs. What is particularly exciting is that it will soon be possible to trace the process all the way from establishment of a signalling centre in a small bud of undifferentiated cells right through to final limb anatomy. The development of the vertebrate limb is a traditional model in which to explore mechanisms involved in pattern formation, and there is accelerating knowledge about the genes involved. One reason why the limb is holding its place in the post-genomic age is that it is rich in pre-genomic embryology. Here, we will focus on recent findings about the aspect of vertebrate limb development concerned with digit pattern across the anteroposterior axis of the limb. This process is controlled by a signalling region in the early limb bud known as the polarizing region. Interactions between polarizing region cells and other cells in the limb bud ensure that a thumb develops at one edge of the hand (anterior) and a little finger at the other (posterior).     

Roles of cell-extrinsic growth factors in vertebrate eye pattern formation and retinogenesis

Formation of the vertebrate visual system involves complex interplays of cell-extrinsic cues and cell-intrinsic determinants. Studies in several vertebrate species demonstrate that multiple classes of signaling molecules participate in pattern formation of the eye and neurogenesis of the retina. Certain signals, such as hedgehog, BMP, and FGF molecules, are repeatedly deployed at varying concentration thresholds and in different cellular contexts. Accumulating evidence reveals a striking conservation of molecular mechanisms regulating the neurogenic process between Drosophila and vertebrate retinas. The remaining challenge is to understand how these well-characterized signaling pathways are activated and integrated to impact eye morphogenesis and retinal progenitor cell fate determination.     

Modeling neural mechanisms of vertebrate habituation: Locus specificity and pattern discrimination

A critical problem in neurobiology is to explain how the central nervous system coordinates pattern discrimination and locus specificity in learning. This problem is investigated in anuran amphibians who demonstrate both locus specificity and pattern discrimination in visual habituation. A neural mechanism is proposed whereby neural circuitry for pattern discrimination is shared by a spatial memory system. Such learning processes are argued to occur in the medial pallium (MP), the anuran's homolog of mammalian hippocampus. Necessary mapping from the shared network to spatial memory is set up by a mechanism that forms topographical connections, with desired orientation determined by activity gradient in presynaptic and postsynaptic layers. The model of MP is tested on both locus and stimulus specific habituation, which involve short-term as well as long-term synaptic plasticity. Successful modeling yields a set of predictions concerning MP organization and learning properties.     

A model generating the pattern of cartilage skeletal elements in the embryonic chick limb.

The development of the vertebrate limb involves the production of a specific external form arising from cell division and other growth processes at the cellular level, and the origin within it of specific patterns of tissues arising by cellular differentiation, of which the pattern of cartilages which pre-figure the limb skeleton is the most striking.In this paper we propose a model for the differentiation (or the preceding determination) process that, using only localized cell to cell interactions, can approximate the cartilage pattern in any limb shape. The model requires cells to modify their metabolism irreversibly at critical threshold levels of a diffusible morphogen which may be made or destroyed by these cells. Restrictions inherent in the successful development of a total limb pattern using this system lead to the prediction that the process is confined to a distal band which has no significant interaction with more proximal regions but within this band the characteristic features of the anterior-posterior axis of the limb develop without additional interactions. Cartilage elements are initiated as single “cells” and expand centrifugally to their final size; these elements developing sequentially along the anterior-posterior axis, showing a distinct polarity of size. The model also predicts that equivalent cartilage elements in all vertebrate limbs will be roughly the same relative size at determination, the extensive range of adult structures arising by differential growth and fusion, possibly controlled by global aspects of the model.It must be emphasized that this model only satisfactorily simulates the anterior-posterior patterning of cartilage elements, the disto-proximal pattern being externally imposed.The final cartilage pattern is shown to be a function of (1) the developing shape of the limb, (2) the position of an initiator region that starts the patterning process and (3) the rate of production of the diffusible morphogen. Using parameters selected with as much realism as possible the model gives a good approximation to the pattern of c cartilages found in the normal chick limb; modifying the shape of the limb to that of the talpid³ mutant produces the characteristics features of the cartilage pattern found in that mutant and modifying the rate of morphogen production simulates patterns resembling those found in some ancestral vertebrate fossil forms.