scholarly journals Cdc42 is required for chondrogenesis and interdigital programmed cell death during limb development

2012 ◽  
Vol 129 (1-4) ◽  
pp. 38-50 ◽  
Author(s):  
Ryo Aizawa ◽  
Atsushi Yamada ◽  
Dai Suzuki ◽  
Tadahiro Iimura ◽  
Hidetoshi Kassai ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Limb Development

Autoregulation of Shh expression and Shh induction of cell death suggest a mechanism for modulating polarising activity during chick limb development

Development ◽  
2000 ◽  
Vol 127 (22) ◽  
pp. 4811-4823 ◽  
Author(s):  
J.J. Sanz-Ezquerro ◽  
C. Tickle
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Sonic Hedgehog ◽  
Limb Development ◽  
Retroviral Vector ◽  
Cellular Mechanism ◽  
Limb Bud ◽  
Drug Induced ◽  
Signalling Molecule ◽  
Vertebrate Limb

The polarising region expresses the signalling molecule sonic hedgehog (Shh), and is an embryonic signalling centre essential for outgrowth and patterning of the vertebrate limb. Previous work has suggested that there is a buffering mechanism that regulates polarising activity. Little is known about how the number of Shh-expressing cells is controlled but, paradoxically, the polarising region appears to overlap with the posterior necrotic zone, a region of programmed cell death. We have investigated how Shh expression and cell death respond when levels of polarising activity are altered, and show an autoregulatory effect of Shh on Shh expression and that Shh affects cell death in the posterior necrotic zone. When we increased Shh signalling, by grafting polarising region cells or applying Shh protein beads, this led to a reduction in the endogenous Shh domain and an increase in posterior cell death. In contrast, cells in other necrotic regions of the limb bud, including the interdigital areas, were rescued from death by Shh protein. Application of Shh protein to late limb buds also caused alterations in digit morphogenesis. When we reduced the number of Shh-expressing cells in the polarising region by surgery or drug-induced killing, this led to an expansion of the Shh domain and a decrease in the number of dead cells. Furthermore, direct prevention of cell death using a retroviral vector expressing Bcl2 led to an increase in Shh expression. Finally, we provide evidence that the fate of some of the Shh-expressing cells in the polarising region is to undergo apoptosis and contribute to the posterior necrotic zone during normal limb development. Taken together, these results show that there is a buffering system that regulates the number of Shh-expressing cells and thus polarising activity during limb development. They also suggest that cell death induced by Shh could be the cellular mechanism involved. Such an autoregulatory process based on cell death could represent a general way for regulating patterning signals in embryos.

Internucleosomal DNA fragmentation and programmed cell death (apoptosis) in the interdigital tissue of the embryonic chick leg bud

1993 ◽  
Vol 106 (1) ◽  
pp. 201-208 ◽  
Author(s):  
V. Garcia-Martinez ◽  
D. Macias ◽  
Y. Ganan ◽  
J.M. Garcia-Lobo ◽  
M.V. Francia ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Dna Fragmentation ◽  
Limb Development ◽  
Light Transmission ◽  
Morphological Changes ◽  
Death Process ◽  
Chondrogenic Potential ◽  
Cell Death Process ◽  
Dying Cells

In this work we have attempted to characterize the programmed cell death process in the chick embryonic interdigital tissue. Interdigital cell death is a prominent phenomenon during limb development and has the role of sculpturing the digits. Morphological changes in the regressing interdigital tissue studied by light, transmission and scanning electron microscopy were correlated with the occurrence of internucleosomal DNA fragmentation, evaluated using agarose gels. Programming of the cell death process was also analyzed by testing the chondrogenic potential of the interdigital mesenchyme, in high density cultures. Our results reveal a progressive loss of the chondrogenic potential of the interdigital mesenchyme, detectable 36 hours before the onset of the degenerative process. Internucleosomal DNA fragmentation was only detected concomitant with the appearance of cells dying with the morphology of apoptosis, but unspecific DNA fragmentation was also present at the same time. This unspecific DNA fragmentation was explained by a precocious activation of the phagocytic removal of the dying cells, confirmed in the tissue sections. From our observations it is suggested that programming of cell death involves changes before endonuclease activation. Further, cell surface changes involved in the phagocytic uptake of the dying cells appear to be as precocious as endonuclease activation.

Macrophage recruitment during limb development and wound healing in the embryonic and foetal mouse

1994 ◽  
Vol 107 (5) ◽  
pp. 1159-1167 ◽  
Author(s):  
J. Hopkinson-Woolley ◽  
D. Hughes ◽  
S. Gordon ◽  
P. Martin
Keyword(s):  
Wound Healing ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Limb Development ◽  
Close Association ◽  
Active Role ◽  
Tissue Remodelling ◽  
Fibroblastic Cells ◽  
Made In

Macrophages play a pivotal role in the adult inflammatory response to wounding. They are directly responsible for cellular debridement and, by providing a source of growth factors and cytokines, they recruit other inflammatory and fibroblastic cells and influence cell proliferation and tissue remodelling. In this paper we investigate the role of macrophages in clearing areas of programmed cell death in the developing embryo and also their role in embryonic and foetal wound healing. Immunocytochemistry using the monocyte/macrophage-specific monoclonal antibody, F4/80, reveals a close association between areas of programmed cell death in the remodelling interdigital regions of the mouse footplate and of F4/80-positive cells, suggesting that monocyte-derived macrophages, and not locally recruited fibroblastic cells, as previously believed, are responsible for phagocytosing and clearing areas of interdigital apoptosis. Our studies of wound healing reveal that macrophages are not recruited to, and therefore cannot be playing an active role in the healing of, excisional wounds made in the mouse embryo at any stage up until E14.5. Beyond this transition stage we see a significant recruitment of macrophages within 12 hours of wounding. We find that macrophages can be attracted to wounds in earlier embryos if the wound results in significant cell death such as after burning.

Programmed cell death is affected in the novel mouse mutant Fused toes (Ft)

Development ◽  
1994 ◽  
Vol 120 (9) ◽  
pp. 2601-2607 ◽  
Author(s):  
F. van der Hoeven ◽  
T. Schimmang ◽  
A. Volkmann ◽  
M.G. Mattei ◽  
B. Kyewski ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Limb Development ◽  
Chromosome 8 ◽  
Mouse Mutant ◽  
Mammalian Development ◽  
D Region ◽  
Left Right Asymmetry ◽  
Development Analysis

We have identified a novel dominant mouse mutant that is characterised by fused toes on the fore limbs and a thymic hyperplasia, in heterozygous animals. Homozygosity of the mutation leads to malformation of the developing brain, lost of the genetic control of left-right asymmetry and to death around day 10 of development. Analysis of both limb development and induction of apoptosis in immature thymocytes in vitro suggest that programmed cell death is affected by the mutation. Since the mutation was caused via a transgene insertion we were able to map it to the D region on mouse chromosome 8. So far, no mutation that affects programmed cell death has been mapped to this chromosome. Thus, this mutation will allow the identification of a novel gene involved in programmed cell death during mammalian development.

The BMP antagonist Gremlin regulates outgrowth, chondrogenesis and programmed cell death in the developing limb

Development ◽  
1999 ◽  
Vol 126 (23) ◽  
pp. 5515-5522 ◽  
Author(s):  
R. Merino ◽  
J. Rodriguez-Leon ◽  
D. Macias ◽  
Y. Ganan ◽  
A.N. Economides ◽  
...  
Keyword(s):  
Cell Death ◽  
Soft Tissue ◽  
Programmed Cell Death ◽  
Limb Development ◽  
Limb Bud ◽  
Central Core ◽  
Limb Outgrowth ◽  
Bmp Antagonists ◽  
And Function ◽  
Bmp Antagonist

In this study, we have analyzed the expression and function of Gremlin in the developing avian limb. Gremlin is a member of the DAN family of BMP antagonists highly conserved through evolution able to bind and block BMP2, BMP4 and BMP7. At early stages of development, gremlin is expressed in the dorsal and ventral mesoderm in a pattern complementary to that of bmp2, bmp4 and bmp7. The maintenance of gremlin expression at these stages is under the control of the AER, ZPA, and BMPs. Exogenous administration of recombinant Gremlin indicates that this protein is involved in the control of limb outgrowth. This function appears to be mediated by the neutralization of BMP function to maintain an active AER, to restrict the extension of the areas of programmed cell death and to confine chondrogenesis to the central core mesenchyme of the bud. At the stages of digit formation, gremlin is expressed in the proximal boundary of the interdigital mesoderm of the chick autopod. The anti-apoptotic influence of exogenous Gremlin, which results in the formation of soft tissue syndactyly in the chick, together with the expression of gremlin in the duck interdigital webs, indicates that Gremlin regulates the regression of the interdigital tissue. At later stages of limb development, gremlin is expressed in association with the differentiating skeletal pieces, muscles and the feather buds. The different expression of Gremlin in relation with other BMP antagonists present in the limb bud, such as Noggin, Chordin and Follistatin indicates that the functions of BMPs are regulated specifically by the different BMP antagonists, acting in a complementary fashion rather than being redundant signals.

scholarly journals Essential mesenchymal role of small GTPase Rac1 in interdigital programmed cell death during limb development

2009 ◽  
Vol 335 (2) ◽  
pp. 396-406 ◽  
Author(s):  
Dai Suzuki ◽  
Atsushi Yamada ◽  
Takanori Amano ◽  
Rika Yasuhara ◽  
Ayako Kimura ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Limb Development ◽  
Small Gtpase

scholarly journals Role of FGFs in the control of programmed cell death during limb development

Development ◽  
2001 ◽  
Vol 128 (11) ◽  
pp. 2075-2084 ◽  
Author(s):  
Juan Antonio Montero ◽  
Yolanda Gañan ◽  
Domingo Macias ◽  
Joaquin Rodriguez-Leon ◽  
Juan Jose Sanz-Ezquerro ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Limb Development ◽  
Positive Influence ◽  
Limb Bud ◽  
Fgf Signaling ◽  
Expression Of Genes ◽  
Combined Action ◽  
Bmp Antagonist

We have investigated the role of FGFs in the control of programmed cell death during limb development by analyzing the effects of increasing and blocking FGF signaling in the avian limb bud. BMPs are currently considered as the signals responsible for cell death. Here we show that FGF signaling is also necessary for apoptosis and that the establishment of the areas of cell death is regulated by the convergence of FGF- and BMP-mediated signaling pathways. As previously demonstrated, cell death is inhibited for short intervals (12 hours) after administration of FGFs. However, this initial inhibition is followed (24 hours) by a dramatic increase in cell death, which can be abolished by treatments with a BMP antagonist (Noggin or Gremlin). Conversely, blockage of FGF signaling by applying a specific FGF-inhibitor (SU5402) into the interdigital regions inhibits both physiological cell death and that mediated by exogenous BMPs. Furthermore, FGF receptors 1, 2 and 3 are expressed in the autopodial mesoderm during the regression of the interdigital tissue, and the expression of FGFR3 in the interdigital regions is regulated by FGFs and BMPs in the same fashion as apopotosis. Together our findings indicate that, in the absence of FGF signaling BMPs are not sufficient to trigger apoptosis in the developing limb. Although we provide evidence for a positive influence of FGFs on BMP gene expression, the physiological implication of FGFs in apoptosis appears to result from their requirement for the expression of genes of the apoptotic cascade. We have identified MSX2 and Snail as candidate genes associated with apoptosis the expression of which requires the combined action of FGFs and BMPs.

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