Spatial and temporal patterns of cell death in limb bud mesoderm after apical ectodermal ridge removal

Rowe, Donene A.; Cairns, John M.; Fallon, John F.

doi:10.1016/0012-1606(82)90241-x

Cited by 91 publications

(47 citation statements)

References 14 publications

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“…In summary, these results suggest that AER activity is required for survival of both the mesenchyme and ectoderm of the limb. In contrast to the surgical ablation studies, where the apoptotic effect in the mesenchyme is immediate (Rowe et al 1982;Dudley et al 2002;Sun et al 2002), we observed a delay in apoptosis in the mesenchyme. We also found that there is a difference in the extent and location of apoptosis depending on the time that the AER is removed.…”

Section: Cell Death and Cell Proliferation In The Ectoderm And Mesenccontrasting

confidence: 99%

“…Removal of the AER by surgical means initiates an immediate apoptotic effect in the distal limb mesenchyme of both the chick and mouse (Rowe et al 1982;Dudley et al 2002;Sun et al 2002). This distal apoptosis may explain the distal truncations observed in the limb following AER removal (Dudley et al 2002).…”

Section: Cell Death and Cell Proliferation In The Ectoderm And Mesencmentioning

confidence: 99%

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EctodermalWnt3/β-cateninsignaling is required for the establishment and maintenance of the apical ectodermal ridge

Barrow¹,

Thomas²,

et al. 2003

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The formation of the apical ectodermal ridge (AER) is critical for the distal outgrowth and patterning of the vertebrate limb. Recent work in the chick has demonstrated that interplay between the Wnt and Fgf signaling pathways is essential in the limb mesenchyme and ectoderm in the establishment and perhaps the maintenance of the AER. In the mouse, whereas a role for Fgfs for AER establishment and function has been clearly demonstrated, the role of Wnt/␤-catenin signaling, although known to be important, is obscure. In this study, we demonstrate that Wnt3, which is expressed ubiquitously throughout the limb ectoderm, is essential for normal limb development and plays a critical role in the establishment of the AER. We also show that the conditional removal of ␤-catenin in the ventral ectodermal cells is sufficient to elicit the mutant limb phenotype. In addition, removing ␤-catenin after the induction of the ridge results in the disappearance of the AER, demonstrating the requirement for continued ␤-catenin signaling for the maintenance of this structure. Finally, we demonstrate that Wnt/␤-catenin signaling lies upstream of the Bmp signaling pathway in establishment of the AER and regulation of the dorsoventral polarity of the limb. The formation of the apical ectodermal ridge (AER) has long been known to play a critical role in the distal outgrowth and patterning of the vertebrate limb. Classical experiments performed by Saunders (1948) demonstrated that surgical removal of this tissue shortly after its formation results in severe truncations of the entire limb, whereas removal at progressively later stages in development allows outgrowth of the more distal elements in a progressive fashion. Given the critical role that the AER plays in limb development, a major focus within the limb field has been to identify molecules that are involved in its establishment and maintenance. The result of this effort has been the discovery that several signaling pathways interact in the establishment of the AER. For example, recent work in the chick has demonstrated that cooperation between the Wnt/␤-catenin and Fgf signaling pathways is essential in establishing the AER. Briefly, the prevailing model is as follows: Wnt/␤-catenin signaling in the limb mesenchyme appears to be required to activate Fgf10 expression in the same tissue (Kawakami et al. 2001). Mesenchymally derived Fgf10 then regulates expression of Wnt3a in the overlying surface ectoderm and later in the subset of ectodermal cells that is destined to give rise to the AER (Kengaku et al. 1997(Kengaku et al. , 1998. Wnt3a signaling is then thought to act through the ␤-catenin pathway to activate the expression of Fgf8 in these pre-AER cells (Kengaku et al. 1998). Fgf8 signaling to the mesenchyme maintains Fgf10 expression, presumably through the mesenchymal Wnt/␤-catenin pathway, thereby completing a regulatory circuit that is critical for maintenance of the AER (see Kawakami et al. 2001).In the mouse, genetic evidence supports the involvement of both Fgf and Wnt/␤-c...

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Section: Cell Death and Cell Proliferation In The Ectoderm And Mesenccontrasting

confidence: 99%

Section: Cell Death and Cell Proliferation In The Ectoderm And Mesencmentioning

confidence: 99%

EctodermalWnt3/β-cateninsignaling is required for the establishment and maintenance of the apical ectodermal ridge

Barrow¹,

Thomas²,

et al. 2003

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“…3T; data not shown). This may explain why cell death in Tcre;Fgfr1 limb buds is not detected in the distal mesenchyme, unlike the situation following AER removal (Dudley et al, 2002;Rowe et al, 1982). We speculate that excess cell death in the Tcre;Fgfr1 limb buds contributes to the later reduction of limb skeleton, in particular the proximal elements.…”

Section: Fgfr1 Expressed In Lbm Is Essential For Cell Survivalmentioning

confidence: 82%

Conditional inactivation of Fgfr1 in mouse defines its role in limb bud establishment, outgrowth and digit patterning

et al. 2005

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Previous studies have implicated fibroblast growth factor receptor 1(FGFR1) in limb development. However, the precise nature and complexity of its role have not been defined. Here, we dissect Fgfr1 function in mouse limb by conditional inactivation of Fgfr1 using two different Cre recombinase-expressing lines. Use of the T (brachyury)-cre line led to Fgfr1 inactivation in all limb bud mesenchyme (LBM) cells during limb initiation. This mutant reveals FGFR1 function in two phases of limb development. In a nascent limb bud, FGFR1 promotes the length of the proximodistal (PD) axis while restricting the dimensions of the other two axes. It also serves an unexpected role in limiting LBM cell number in this early phase. Later on during limb outgrowth, FGFR1 is essential for the expansion of skeletal precursor population by maintaining cell survival. Use of mice carrying the sonic hedgehogcre(Shhcre) allele led to Fgfr1 inactivation in posterior LBM cells. This mutant allows us to test the role of Fgfr1in gene expression regulation without disturbing limb bud growth. Our data show that during autopod patterning, FGFR1 influences digit number and identity, probably through cell-autonomous regulation of Shhexpression. Our study of these two Fgfr1 conditional mutants has elucidated the multiple roles of FGFR1 in limb bud establishment, growth and patterning.

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“…During limb bud initiation, BMP signaling is crucial for the induction of the apical ectodermal ridge (AER), a specialized epithelial structure located at the distal tip of the developing limb that controls formation of the proximal -distal axis from body center toward tips of appendages (Johnson and Tabin 1997;Martin 1998;Ahn et al 2001). Early ablation of the AER or conditional inactivation of BMP signaling in the ectoderm leads to limb truncation (Saunders 1948;Summerbell et al 1973;Rowe et al 1982;Ahn et al 2001). The AER functions to initiate and maintain normal gene expression patterns in the progress zone (PZ), an area of undifferentiated cells in the mesoderm directly underlying the AER, and is furthermore re-quired for the maintenance of SHH expression within the zone of polarizing activity (ZPA), a crucial signaling center located at the posterior margin of the limb that controls anterior-posterior pattering.…”

Section: Roles Of Tgf-b and Bmp Signaling In Limb Formation And Digitmentioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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The transforming growth factor b (TGF-b) family of signaling molecules, which includes TGF-bs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-b family members play different roles in these tissues, and their activities are often balanced with those of other TGF-b family members and by interactions with other signaling pathways. Perturbations in TGF-b family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-b family of signaling mediators and the extracellular matrix in connective tissues.T he transforming growth factor b (TGF-b) family of cytokines comprises the three TGF-b proteins (TGF-b1, TGF-b2, and TGFb3) and related growth and differentiation factors such as activins, inhibins, bone morphogenic proteins (BMPs), and growth and differentiation factors (GDFs). These molecules play critical roles both in normal development and in several pathological conditions, including inflammation, fibrosis, and cancer (reviewed in Li and Flavell 2006;Gordon and Blobe 2008;Ikushima and Miyazono 2010). This review focuses on the role of these proteins in development and homeostasis of the skeleton and other connective tissues (summarized in Fig. 1) and on the diseases that ensue when these pathways are altered. Aberrant signaling in these pathways has been associated with common connective 6 These authors contributed equally to this work.

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Spatial and temporal patterns of cell death in limb bud mesoderm after apical ectodermal ridge removal

Cited by 91 publications

References 14 publications

EctodermalWnt3/β-cateninsignaling is required for the establishment and maintenance of the apical ectodermal ridge

EctodermalWnt3/β-cateninsignaling is required for the establishment and maintenance of the apical ectodermal ridge

Conditional inactivation of Fgfr1 in mouse defines its role in limb bud establishment, outgrowth and digit patterning

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

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