Expression of the Connexin43 Gap Junctional Protein in Tissues at the Tip of the Chick Limb Bud Is Related to the EpitheliaI-Mesenchymal Interactions That Mediate Morphogenesis
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Apical ectodermal ridge
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Mesenchyme
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Abstract Scatter factor/hepatocyte growth factor (SF/HGF) is known to be involved in the detachment of myogenic precursor cells from the lateral dermomyotomes and their subsequent migration into the newly formed limb buds. As yet, however, nothing has been known about the role of the persistent expression of SF/HGF in the limb bud mesenchyme during later stages of limb bud development. To test for a potential role of SF/HGF in early limb muscle patterning, we examined the regulation of SF/HGF expression in the limb bud as well as the influence of SF/HGF on direction control of myogenic precursor cells in limb bud mesenchyme. We demonstrate that SF/HGF expression is controlled by signals involved in limb bud patterning. In the absence of an apical ectodermal ridge (AER), no expression of SF/HGF in the limb bud is observed. However, FGF-2 application can rescue SF/HGF expression. Excision of the zone of polarizing activity (ZPA) results in ectopic and enhanced SF/HGF expression in the posterior limb bud mesenchyme. We could identify BMP-2 as a potential inhibitor of SF/HGF expression in the posterior limb bud mesenchyme. We further demonstrate that ZPA excision results in a shift of Pax-3-positive cells towards the posterior limb bud mesenchyme, indicating a role of the ZPA in positioning of the premuscle masses. Moreover, we present evidence that, in the limb bud mesenchyme, SF/HGF increases the motility of myogenic precursor cells and has a role in maintaining their undifferentiated state during migration. We present a model for a crucial role of SF/HGF during migration and early patterning of muscle precursor cells in the vertebrate limb.
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Abstract The vertebrate limb appears as an outgrowth in the flank of the embryonic body. Initially it consists of a mesenchymal core covered by a layer of ectoderm. During the elongation of the limbs the apparently homogeneous population of the mesenchymal cells gives rise to different cell types: cartilage, bone, muscle, and other tissues, that develop in appropriate spatial relationships to constitute the developed limb. From grafting experiments that have been performed mainly in the chick, it appears that two mechanisms are involved in the formation of the proximodistal (from the base to the tip) and the anteroposterior (from the thumb to the little finger) pattern of the limbs. Development of the proximodistal axis involves the mesenchymal cells in the distal tip of the limbs, which through a mesenchymal-ectodermal interaction, induce the overlying ectoderm to thicken. This results in the formation of a pseudostratified columnar epithelium known as the apical ectodermal ridge (AER). This ridge appears to be essential for the outgrowth of the limbs and grafting experiments have shown that its removal results in a truncated limb (Zwilling 1956; Saunders and Gasseling 1968). Once the AER is formed it exerts an inductive influence on the underlying mesenchyme, which grows rapidly and differentiates. Positional values along the proximodistal axis are defined by the time spent in an area of undifferentiated mesenchyme under the tip of the bud, known as the progress zone (Summerbell et al. 1973). Cells leaving the progress zone at early times differentiate into proximal structures, while the cells that leave the progress zone later give rise to distal structures.
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MOLECULAR AND CELLULAR MECHANISMS WHEREBY THE APICAL ECTODERMAL RIDGE (AER), VIA WNT5A, MEDIATES DIRECTIONAL MIGRATION OF THE ADJACENT MESENCHYME DURING VERTEBRATE LIMB DEVELOPMENT Kate E Kmetzsch Department of Physiology and Developmental Biology Master of Science The vertebrate embryonic limb is a key model in elucidating the genetic basis underlying the three dimensional morphogenesis of structures. Despite the wealth of insights that have been generated from this model, many long-standing questions remain. For example, it has been known for over 70 years that the apical ectodermal ridge (AER) of the embryonic limb is essential for distal outgrowth and patterning of the adjacent limb mesenchyme. The mechanisms whereby the AER does accomplish outgrowth and patterning are still poorly understood. We propose that secreted FGFs from the AER activate Wnt5a expression in gradient fashion, which in turn provides an instructional cue to direct outgrowth in the direction of increasing Wnt5a expression (i.e. toward the distal tip of the limb). In vivo and in vitro models were used to test this hypothesis. We placed Wnt5a expressing L-cell implants into stage 23 chick limb buds and demonstrate that labeled mesenchyme cells grow toward the source of Wnt5a. Purified Wnt5a soaked heparin bead implants have only a marginal effect on directed growth of the adjacent mesenchyme, whereas a greater effect was seen with beads soaked in Wnt5a conditioned media. Using an in vitro model where cultured limb mesenchyme cells were subjected to a gradient of conditioned Wnt5a media or purified Wnt5a, we show no specific migratory direction. However, clusters of cells tended to move toward the source of Wnt5a indicating that it might be necessary for the cells to be in complete contact to respond to the Wnt5a signal. Taken together, our results suggest that Wnt5a is sufficient to direct limb mesenchyme. This finding has given support to a new model of limb development proposed by our lab and referred to as the Mesenchyme Recruitment Model.
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Abstract The apical ectodermal ridge plays a central role in limb development through its interactions with the underlying mesenchyme. Removal of the AER results in cessation of limb outgrowth and leads to truncation of the limb along the proximo‐distal axis. The many functions attributed to the ridge include maintenance of the progress zone mesenchyme. Here, cells are stimulated to proliferate, are maintained in an undifferentiated state, and are assigned progressively more distal positional values as the limb grows. The AER also functions to maintain the activity of the polarizing region, a region of mesenchyme which is thought to provide the primary signal for patterning along the antero‐posterior axis. We have begun to explore the function of fibroblast growth factor‐4 (FGF‐4) during limb development. FGF‐4, which encodes an efficiently secreted protein, is expressed in the AER. We have previously demonstrated that FGF‐4 protein can stimulate limb mesenchyme proliferation and can induce the expression of a downstream homeobox gene, Evx‐1 (homologue of the Drosophila even‐skipped gene), that is normally regulated by a signal from the AER. To determine to what extent FGF‐4 protein can substitute for the AER to allow normal limb outgrowth, we performed experiments on the developing chick limb in ovo. Remarkably, we find that after AER removal, the FGF‐4 protein can provide all the signals required for virtually normal outgrowth and patterning of the limb. Further studies indicate that proliferation of progress zone cells is not sufficient, and that an additional signal is produced by the posterior mesenchyme in response to FGF‐4 which enables progress zone cells to acquire progressively more distal fates. Thus FGF‐4 maintains progress zone activity through a combination of at least two signals—one that acts directly on progress zone cells to stimulate their proliferation, and one that acts indirectly by maintaining the production of patterning signal(s) by the posterior mesenchyme. We further show that failure of the posterior mesenchyme to produce this signal correlates with failure to maintain polarizing activity. This raises the possibility that the signal produced by the posterior mesenchyme and required for progressive proximo‐distal limb patterning is identical to the polarizing activity. Further experiments demonstrate that retinoic acid, which mimics the activity of the polarizing region, can supply this signal. In conclusion, the finding that a single growth factor can serve as both the direct and indirect signals required to maintain progress zone activity provides a simple mechanism for ensuring that growth and pattern formation are linked in the developing limb. © 1994 Wiley‐Liss, Inc.
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Abstract Multiple studies indicate that quantitative control of the levels of all‐ trans ‐retinoic acid (RA) in the vertebrate embryo is necessary for correct development. The function of RA in cells is regulated by a number of coordinated mechanisms. One of those mechanisms involves controls on the rate of RA catabolism. Recently, enzymes capable of catabolizing RA were found to constitute a new family, called CYP26, within the cytochrome P450 superfamily. CYP26 homologues have been isolated from human, mouse, zebra fish, and recently from the chick. In this study, we examined the regulation of chicken CYP26 ( cCYP26 ) expression by RA during the early phase of chick limb outgrowth. In the anterior limb mesenchyme and apical ectodermal ridge (AER), cCYP26 expression was induced in a concentration dependent manner by implanting beads soaked in 0.1, 1, and 5 mg/ml RA. The RA‐induced expression of cCYP26 in anterior limb mesenchyme and the AER was detected as early as 1 hr after treatment and was not affected by the presence of cycloheximide. In contrast to the anterior limb, the induction of cCYP26 was dramatically reduced (or absent) when RA beads were implanted in the posterior limb mesenchyme. Furthermore, induction of cCYP26 expression in the anterior mesenchyme was inhibited by transplantations of the zone of polarizing activity (ZPA) and by Shh‐soaked beads. Our data suggest that different mechanisms regulate retinoid homeostasis in the AER and mesenchyme during limb bud outgrowth. J. Exp. Zool. 290:136–147, 2001 . © 2001 Wiley‐Liss, Inc.
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Cellular adhesion is fundamental to the behaviour of cell populations during embryonic development and serves to establish correct tissue pattern and architecture. The cadherin superfamily of cell adhesion proteins regulates cellular organization and additionally influences intracellular signalling cascades. Here we present for the first time a detailed account of chick Fat-1 gene expression during embryogenesis visualised by whole-mount in situ hybridisation. In part, we focus on the expression pattern in limb buds that has not been accurately documented. While Fat-1 is generally expressed in epithelial tissues and its Drosophila counterpart Fat-like regulates formation of ectodermally-derived organs, in limb buds we have found that chick Fat-1 is uniquely restricted to mesenchyme. This Fat-1 expression pattern is remarkably dynamic throughout tissue differentiation, limb maturation and pattern formation. Diffuse expression of Fat-1 begins at stage HH17 as the limb bud is forming. It then becomes more proximal as the limb bud grows and is expressed within both tendon and muscle progenitors in the dorsal and ventral subectodermal mesenchyme. Later, Fat-1 transcripts were more abundant in anterior and posterior domains of the limb bud. During hand plate formation, Fat-1 transcripts were expressed in the mesenchyme adjacent to the wrist joint zone and in the interdigit mesenchyme.
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The apical ectodermal ridge (AER) is a specialized thickening of the distal limb mesenchyme that has been demonstrated to support limb outgrowth and proper limb development. The homeobox gene, Max-1, is associated with the distal limb mesenchyme (progress zone) and its expression depends upon the presence of the AER in chick limbs. We demonstrate here that the expression of Max-1 is dependent upon the limb ectoderm in the mouse, but that the inductive capacity of murine limb ectoderm is not restricted to the AER. Msx-1 can also he maintained in limb mesenchyme by the substitution of FGF 4 for the ectoderm; however, we see that local cell-cell interactions are required for high levels of expression. Disruption of cell-call interactions in the limb mesenchyme results in a dramatic decrease in Msx-1 levels and a precocious expression of MyoD1, suggesting that the limb environment represses differentiation and promotes cell proliferation during early development. BMP 4 and FGF 2 can also maintain Msx-1 expression in limb mesenchyme as well as retinoic acid which is usually associated with polarizing activity in the early limb. Max-2 expression does not appear to be dependent upon cell-cell interactions as measured in these experiments. Taken together, our data suggest that the expression of Max-1, but not Max-2, not only requires factors from the limb ectoderm, but also relies upon cues from local cell interactions and that the spatial distribution of inductive capacities in limb ectoderm differs between the avian and murine systems.
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