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TGF-beta is required for programmed cell death in interdigital webs of the developing mouse limb
Nicole Dünker1, Kai Schmitt, Kerstin Krieglstein
1Department of Anatomy and Cell Biology, Building 61, University of Saarland, D-66421, Homburg/Saar, Germany. nduenke@gwdg.de
Abstract:
During limb formation massive cell death in the mesenchyme of the interdigital spaces accompanies the formation of free digits. Members of the transforming growth factor beta (TGF-) superfamily were discussed to play a key role in cell-cell interactions, important in the regulation of programmed cell death (PCD). TGF-beta itself is believed to be involved in epithelial-mesenchymal interactions. Here, we demonstrate that PCD is significantly reduced in interdigital spaces of the developing limbs of Tgfbeta2-/-Tgfbeta3-/- double knockouts. The regression of interdigital webs seems to be doses-dependent as interdigital mesenchyme is at least partly reduced in Tgfbeta2-/-Tgfbeta3+/- mutants, whereas interdigital zones of Tgfbeta2-/-Tgfbeta3-/- double knockouts reveal only minimal signs of regression. We conclude that TGF- is a critical extrinsic regulator of PCD.
Insights
Transforming growth factor beta (TGF-β) is critical for programmed cell death (PCD) during limb development. Loss of TGF-β2 and TGF-β3 significantly reduces PCD, hindering digit formation and web regression.
Area of Science:
- Developmental Biology
- Molecular Biology
- Genetics
Background:
- Limb formation involves programmed cell death (PCD) in interdigital spaces.
- Transforming growth factor beta (TGF-β) superfamily members are implicated in cell-cell interactions and PCD regulation.
- TGF-β is suggested to mediate epithelial-mesenchymal interactions during development.
Purpose of the Study:
- To investigate the role of TGF-β2 and TGF-β3 in regulating PCD during limb development.
- To determine the effect of TGF-β2 and TGF-β3 deficiency on interdigital web regression.
Main Methods:
- Analysis of limb development in Tgfbeta2-/-Tgfbeta3-/- double knockout mice.
- Assessment of interdigital mesenchyme regression and PCD in mutant embryos.
- Examination of dose-dependent effects using Tgfbeta2-/-Tgfbeta3+/- mutants.
Main Results:
- Programmed cell death (PCD) was significantly reduced in the interdigital spaces of Tgfbeta2-/-Tgfbeta3-/- double knockout limbs.
- Interdigital web regression was dose-dependently affected by TGF-β2 and TGF-β3 levels.
- Tgfbeta2-/-Tgfbeta3+/- mutants showed partial reduction in interdigital mesenchyme, while double knockouts exhibited minimal regression.
Conclusions:
- TGF-β signaling is essential for regulating PCD during limb development.
- TGF-β2 and TGF-β3 play a critical role in the regression of interdigital webs.
- TGF-β acts as a crucial extrinsic regulator of programmed cell death in this context.