Abstract
Interdigital cell death is a physiological regression process responsible for sculpturing the digits in the embryonic vertebrate limb. Changes in the intensity of this degenerative process account for the different patterns of interdigital webbing among vertebrate species. Here, we show that Reelin is present in the extracellular matrix of the interdigital mesoderm of chick and mouse embryos during the developmental stages of digit formation. Reelin is a large extracellular glycoprotein which has important functions in the developing nervous system, including neuronal survival; however, the significance of Reelin in other systems has received very little attention. We show that reelin expression becomes intensely downregulated in both the chick and mouse interdigits preceding the establishment of the areas of interdigital cell death. Furthermore, fibroblast growth factors, which are cell survival signals for the interdigital mesoderm, intensely upregulated reelin expression, while BMPs, which are proapototic signals, downregulate its expression in the interdigit. Gene silencing experiments of reelin gene or its intracellular effector Dab-1 confirmed the implication of Reelin signaling as a survival factor for the limb undifferentiated mesoderm. We found that Reelin activates canonical survival pathways in the limb mesoderm involving protein kinase B and focal adhesion kinase. Our findings support that Reelin plays a role in interdigital cell death, and suggests that anoikis (apoptosis secondary to loss of cell adhesion) may be involved in this process.
Highlights
(VLDLR) and apolipoprotein E receptor 2 (ApoER2) inducing the phosphorylation of the intracellular adaptor protein Disabled-1 (Dab-1),[24,25,26] which in turn activates downstream effectors involved in cytoskeletal reorganization, cell migration and cell survival.[27]
We show that Reelin and its intracellular signaling protein DAB-1 are highly expressed in the undifferentiated mesoderm during digit formation and are downregulated in the interdigits preceding the onset of apoptosis
The reelin gene was identified in a complementary DNA library generated from the interdigital mesoderm of the developing chick limb in the stages preceding cell death.[15]
Summary
(VLDLR) and apolipoprotein E receptor 2 (ApoER2) inducing the phosphorylation of the intracellular adaptor protein Disabled-1 (Dab-1),[24,25,26] which in turn activates downstream effectors involved in cytoskeletal reorganization, cell migration and cell survival.[27]. We show that Reelin and its intracellular signaling protein DAB-1 are highly expressed in the undifferentiated mesoderm during digit formation and are downregulated in the interdigits preceding the onset of apoptosis. In accordance with a pro-survival role of this signaling pathway, reelin gene expression is upregulated in vivo by local treatment with FGFs which are survival signals for the interdigital mesoderm and down-regulated by BMPs which are pro-apoptotic signals. Reelin and interdigital cell death MJ Dıaz-Mendoza et al increases cell death in primary cultures of the undifferentiated mesoderm. We identified focal adhesion kinase (FAK) and protein kinase B (AKT) as potential mediators of the pro-survival effect of Reelin signaling
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