Vertebrate limb development

doi:10.1016/0959-437X(95)90052-I

Current Opinion in Genetics & Development

Volume 5, Issue 4, August 1995, Pages 478-484

https://doi.org/10.1016/0959-437X(95)90052-I Get rights and content

Abstract

The recent identification of Wnt-7a as a signalling molecule in dorsal/ventral patterning means that we now have a known signal for control of each of the three limb axes. Fibroblast growth factors can allow proximal/distal patterning and Sonic hedgehog gene expression signals anterior/posterior patterning. Networks of these signals not only coordinate cell responses, but also mutually maintain each other. A positive feedback loop is established which coordinates expression of Sonic hedgehog in mesenchyme cells of the polarizing region and Fgf-4 expression in overlying apical ridge ectoderm. Wnt-7a expression in dorsal ectoderm also influences Sonic hedgehog expression in the polarizing region. Initiation of development of a complete limb can be achieved with just one signal, a growth factor.

References (31)

L Wolpert
Positional information and pattern formation
Curr Top Dev Biol
(1971)
L Niswander et al.
FGF-4 replaces the apical ectodermal ridge and directs outgrowth and patterning of the limb
Cell
(1993)
RD Riddle et al.
Sonic hedgehog mediates the polarizing activity of the ZPA
Cell
(1993)
PH Crossley et al.
The mouse Fgf-8 gene encodes a family of polypeptides and is expressed in regions that direct outgrowth and patterning in the developing embryo
Development
(1995)
J Heemskerk et al.
Drosophila hedgehog acts as a morphogen in cellular patterning
Cell
(1994)
CN Dealey et al.
Wnt-5a and Wnt-7a are expressed in the developing chick limb bud in a manner suggesting roles in pattern formation along the proximo-distal and dorsoventral axes
Mech Dev
(1993)
J-C Izpisua-Belmonte et al.
Expression of Hox-4 genes in the chick wing links pattern formation to the epithelial-mesenchymal interactions that mediate growth
EMBO J
(1992)
MJ Cohn et al.
Fibroblast growth factors induce additional limb development from the flank of chick embryos
Cell
(1995)
A Hornbruch et al.
The spatial and temporal distribution of polarizing activity in the flank of pre-limb-bud stages in the chick embryo
Development
(1991)
JF Fallon et al.
FGF-2: apical ectodermal ridge outgrowth signal for chick limb development
Science
(1994)

DT Chang et al.

Products, genetic linkage and limb patterning activity of a murine hedgehog gene

Development

(1994)

BA Parr et al.

Dorsalizing signal Wnt-7a required for normal polarity of D-V and A-P axes of mouse limb

Nature

(1995)

M Heikinheimo et al.

Fgf-8 expression in the post-gastrulation mouse suggests roles in the development of the face, limbs and central nervous system

Mech Dev

(1994)

K Peters et al.

Targeted expression of a dominant negative FGF receptor blocks branching morphogenesis and epithelial differentiation of the mouse lung

EMBO J

(1994)

SV Bryant et al.

Retinoic acid, local cell-cell interactions, and pattern formation in vertebrate limbs

Dev Biol

(1992)

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In vivo bone remodeling involves the recruitment and replication of mesenchymal precursors of osteoblasts, their differentiation into pre-osteoblasts, osteoblasts and mature osteoblasts, ultimately resulting in the accumulation and mineralization of the extracellular matrix. During the initial development of the vertebrate skeleton, the mesenchyme receives patterning signals that determine the shape, size and number of mesenchymal condensations.2 With the exception of the cranial base synchondroses and the temporomandibular joints (TMJs), all the articulations between the bones of the skull are fibrous joints.
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Extended exposure to Sonic hedgehog is required for patterning the posterior digits of the vertebrate limb
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Sonic hedgehog (Shh) is a key signal in establishing different digit fates along the anterior–posterior axis of the vertebrate limb bud. Although the anterior digits appear to be specified by differential concentrations of Shh in a traditional, morphogen-like response, recent studies have suggested that posterior digits are specified by an extended time of exposure to Shh rather than, or in addition to, a threshold concentration of Shh. This model for digit patterning depends upon continued Shh signaling in the posterior limb through mid-to-late bud stages. We find that cyclopamine, a potent antagonist of Shh signaling, can down-regulate hedgehog target genes in the posterior limb throughout the time Shh is expressed, indicating that continued active Shh signaling indeed takes place. To further explore the relative roles of time and concentration of Shh during limb development, we carried out two additional series of experiments. To test the effect of limiting the time, but not the amount of Shh produced, we treated chick embryos with the hedgehog antagonist cyclopamine at various stages of limb development. We find that short exposures to Shh result in specification of only the most anterior digits and that more posterior digits are specified sequentially with increasing times of uninterrupted Shh activity. To test the effect of limiting the level of Shh produced, but not the time of exposure, we genetically modified Shh production in mice. As previously shown, reducing both the concentration of Shh produced and the duration of Shh exposure results in a loss of posterior digits. We find that maintaining a low level of Shh production throughout the normal time frame of ZPA signaling results in a near complete restoration of the posterior-most digits. These data are consistent with, and lend additional support to, the model that concentration of Shh seen and duration of exposure both contribute to the dose-dependent specification of digit identities, but for the posterior-most digits the temporal component is the more critical parameter.
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The hands and feet of a newborn baby are a beautiful reminder of the complexity of embryonic patterning. Classical studies on how these structures form have led to a theoretical framework for understanding, in general, how discrete groups of cells can instruct differential fates across a wider field through the action of long-range signals. The discovery just more than a decade ago that localized expression of Sonic hedgehog (Shh) differentially patterns structures across the limb field, resulting in digits with unique characteristics, provided a starting point for readdressing these models at a molecular level. Current research has revealed unexpected complexity in how a gradient of Shh activity is both established and received, prompting re-evaluation of the nature of patterning mechanisms within the limb.
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It is well established that local modification of extracellular matrix (ECM) hyaluronan composition is vital in the regulation of cell behavior. Indeed, the formation of articulating chick joint cavities, which requires mechanical stimuli derived from skeletal movement, is dependent upon the accumulation of an ECM rich in hyaluronan (HA). However, the mechanisms responsible for such precise mechano-dependent regulation of cell behavior and the formation of a HA-rich ECM remain undefined. Here we show that extracellular-regulated kinase 1/2 (ERK1/2) is selectively activated in cells at sites of cavity formation and activity diminished by in ovo immobilization that induces cartilaginous fusion across presumptive joint interzones. In vitro analyses offer mechanistic support for the role of mechanical stimuli in promoting a MEK-dependent activation of ERK1/2. In addition, our direct regulation of ERK1/2 phosphorylation status via modulation of its up-stream “classical cascade” activator either pharmacologically or by transfection with dominant negative or constitutively active Mek confirms the essential role for ERK1/2 activation in the elaboration of HA-rich pericellular matrices. Together, our findings demonstrate that the MEK-ERK pathway, regulated by mechanical stimuli, controls HA-rich matrix assembly. The precision of ERK1/2 activation selectively distinguishing cells at the joint line suggests that it directly contributes to the loss of tissue cohesion essential for generating HA-rich cavities between joint elements during their development.

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View full text

Pattern formation and developmental mechanismVertebrate limb development

Abstract

Curr Top Dev Biol

Cell

Cell

Development

Cell

Mech Dev

EMBO J

Cell

Development

FGF-2: apical ectodermal ridge outgrowth signal for chick limb development

Science

Products, genetic linkage and limb patterning activity of a murine hedgehog gene

Development

Dorsalizing signal Wnt-7a required for normal polarity of D-V and A-P axes of mouse limb

Nature

Fgf-8 expression in the post-gastrulation mouse suggests roles in the development of the face, limbs and central nervous system

Mech Dev

Targeted expression of a dominant negative FGF receptor blocks branching morphogenesis and epithelial differentiation of the mouse lung

EMBO J

Retinoic acid, local cell-cell interactions, and pattern formation in vertebrate limbs

Dev Biol

Pattern formation and developmental mechanism
Vertebrate limb development