Development of fragmented and of dissociated limb bud mesoderm

Zwilling, Edgar

doi:10.1016/0012-1606(64)90012-0

Cited by 106 publications

(37 citation statements)

References 20 publications

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“…Despite the complexities mentioned, a reactor-diffusion-like mechanism remains the most compelling basis for the generic vertebrate limb skeletal pattern for the following reasons: 1) randomized limb mesenchymal cells with disrupted gradients of Hox proteins, Shh, etc., give rise to digit-like structures in vivo (Zwilling, 1964;Ros et al, 1994) and of discrete, regularly spaced cartilage nodular or stripe-like arrangements in vitro (Downie and Newman, 1994;Kiskowski et al, 2004;Christley et al, 2007); 2) the pattern of precartilage condensations in limb mesenchyme in vitro changes in a fashion consistent with a reactor-diffusion mechanism (and not with an alternative mechanochemical mechanism) when the density of the surrounding matrix is varied (Miura and Shiota, 2000b); 3) exogenous FGF perturbs the kinetics of precartilage condensation in vitro in a fashion consistent with a role for this factor in regulating the inhibitor in a reactor-diffusion-type model (Miura and Maini, 2004); 4) the ''thick-thin'' pattern of digits in the Doublefoot mouse mutant can be accounted for by the assumption that the normal pattern is governed by a reactor-diffusion process, the parameters of which are modified by the mutation (Miura et al, 2006); 5) simultaneous knockout of Shh and its inhibitory regulator Gli3 in mice yields limbs with numerous extra digits (Litingtung et al, 2002), suggesting a default propensity of the limb mesenchyme to generate regularly spaced repetitive elements of indefinite number. A reactor-diffusion-type mechanism is the most plausible basis for this.…”

Section: Evidence For Activator-inhibitor Dynamics In Limb Bud Mesencmentioning

confidence: 99%

Activator‐inhibitor dynamics of vertebrate limb pattern formation

Newman

Bhat

2007

Birth Defects Research Pt C

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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.

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Section: Evidence For Activator-inhibitor Dynamics In Limb Bud Mesencmentioning

confidence: 99%

Activator‐inhibitor dynamics of vertebrate limb pattern formation

Newman

Bhat

2007

Birth Defects Research Pt C

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“…Recombinant limbs are composed of randomized and reaggregated mesenchymal cells covered by an intact limb ectoderm, and have been utilized as an experimental tool to examine pattern specification and patterning mechanisms during limb development (see Zwilling, 1964;FernandezTeran et al, 1999). Recombinant limb buds made from wing mesenchyme vs leg mesenchyme are distinct in their respective capacities to form limb structures.…”

Section: Discussionmentioning

confidence: 99%

Differential Cell Affinity and Sorting of Anterior and Posterior Cells during Outgrowth of Recombinant Avian Limb Buds

Omi

Anderson

Muneoka

2002

Developmental Biology

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To examine the role of position-specific differences in cell-cell affinity, recombinant limb buds composed of dissociated and reaggregated cells derived from anterior (A) and posterior (P) limb bud fragments were analyzed. Dissociated anterior and/or posterior cells were differentially labeled, and their behavior was analyzed during recombinant limb bud outgrowth. We find that anterior and posterior cells sort out from one another to form alternating anterior and posterior stripes of cells that extend distally along the proximal-distal axis. These alternating stripes are prominent across the A/P axis in whole-mount preparations of recombinant limb buds after 48 h of outgrowth when the presumptive autopod is dorsal-ventrally flattened and digit rudiments are not evident. After 96 h, when digital and interdigital regions are clearly defined, we find evidence that A/P stripes do not follow obvious anatomical boundaries. The formation of A/P stripes is not inhibited by grafts of ZPA tissue, suggesting that polarizing activity does not influence cell-cell affinity early in limb outgrowth. In vitro studies provide evidence that cell sorting is not dependent on the limb bud ectoderm or the AER; however, cells sort out without organizing into stripes. Gene expression studies using anterior-specific (Alx-4) and posterior-specific (Shh, Bmp-2, and Hoxd-13) marker genes failed to reveal expression domains that corresponded to stripe formation. Control recombinant limb buds composed of anterior, central, or posterior mesenchyme formed digits in a position-specific manner. A/P recombinant limb buds that develop to later stages form digits that are characteristic of central recombinant limbs. These data provide the first definitive evidence of A/P cell sorting during limb outgrowth in vivo and suggest that differential cell affinities play a role in modulating cell behavior during distal outgrowth.

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“…19.1. Isolated and dissociated limb bud tissue can reconstitute limblike skeletal patterns in vivo (Zwilling 1964;Ros et al 1994), and nodular patterns of . Early cartilage, including precartilage condensations, is shown in light gray; definitive cartilage is shown in dark gray.…”

Section: The Turing Mechanism In Limb Developmentmentioning

confidence: 99%

Development and Evolution: The Physics Connection

Newman

2014

Boston Studies in the Philosophy and History of Science

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Development of fragmented and of dissociated limb bud mesoderm

Cited by 106 publications

References 20 publications

Activator‐inhibitor dynamics of vertebrate limb pattern formation

Activator‐inhibitor dynamics of vertebrate limb pattern formation

Differential Cell Affinity and Sorting of Anterior and Posterior Cells during Outgrowth of Recombinant Avian Limb Buds

Development and Evolution: The Physics Connection

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