raw透過限制Dpp的表現抑制果蠅心臟細胞的死亡
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2009
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Raw是djnk作用途徑的組成分子之一，且在背部癒合時能夠調控dpp在leading edge的表現。raw突變的果蠅胚胎中，Dpp的表現範圍於胚胎發育中期(第12-14時期)時將會顯著擴張。以往的研究證實在中胚層表現過多的dpp會造成心臟先驅細胞的增生，而raw突變的果蠅在第13-14時期時，心臟先驅細胞也會過度表現，且心臟細胞的增生與過度表現的dpp於時空上是一致的。然而到了胚胎發育的晚期，多種類型的心臟細胞表現卻都消失。因為在raw突變的果蠅胚胎中，在背部的外胚層和中胚層都有大量的細胞死亡，因此我們假設心臟細胞的缺失是由細胞凋亡所引起。另一方面，因為死亡的細胞和過度表現的dpp於時空上也有高度的一致性，表示過量的dpp可能是造成果蠅細胞凋亡的原因。在本研究中，我們也證實單獨表現dpp即可造成細胞凋亡，且細胞死亡的程度與dpp的活性成正比。此外我們也在中胚層表現顯性抑制的dTAK1而減少了raw突變中的心臟細胞凋亡，證實dpp是透過dTAK1而造成細胞的死亡。另一方面dTAK1也被證實能夠活化dpp及djnk的表現，這代表中胚層的djnk訊號將會持續的被來自背部外胚層大量表現的dpp所活化。再者，我們也證實表現顯性抑制的p53可以減少因為在中胚層大量表現dTAK1所造成的細胞凋亡。因為在哺乳動物中，BMP訊息路徑所造成的細胞凋亡也由dTAK1所中介，因此由BMP所造成的細胞凋亡於演化上應該是非常保守的。
Raw, a component of djnk signaling pathway, plays a role in dorsal closure by modulating expression of Dpp in epidermal cells at the leading edge. The expression domain of Dpp was found to be markedly expanded in raw mutant embryos at stages 12-14. Similar to a previous study, we found that deficit in raw causes overproduction of cardial precursor cells in Drosophila at stages 13-14 which is concurrent with the ectopic Dpp activity. This result can be explained because mesodermal overexpression of dpp has shown to promote formation of cardial precursors. Nevertheless, various cardial cells are disappeared in raw mutant embryos at stages 15-16. We hypothesized that loss of cardial cell is resulted from apoptosis in late raw mutants. Indeed, excessive cell death, particularly in dorsal ectoderm and dorsal mesoderm, were observed in raw mutant embryos. Since the distribution of apoptotic cell coincides well with both the spatial and temporal expression domain of ectopic dpp, suggesting that ectopic dpp may induce cardial cell apoptosis in Drosophila. We show that increasing in Dpp activity alone promotes apoptosis in dose-dependent manner. In addition, we show that Dpp induced apoptosis is mediated through dTAK1, as mesodermally expression of a dominant negative dTAK1 suppresses apoptosis of cardial cell in raw mutation embryos. Interestingly, dTAK has shown to activate expression of djnk and dpp. This means that djnk signaling is constitutively activated in mesoderm by ectopic dpp from dorsal ectoderm. We have further demonstrated mesodermal dTAK1 induced apoptosis can be suppressed by expression of dominant negative p53. Since BMP signaling pathway induces apoptosis has also been shown to be mediated through TAK1 in mammals. Thus, the BMP induced apoptosis pathway may be evolutionarily conserved.
Raw, a component of djnk signaling pathway, plays a role in dorsal closure by modulating expression of Dpp in epidermal cells at the leading edge. The expression domain of Dpp was found to be markedly expanded in raw mutant embryos at stages 12-14. Similar to a previous study, we found that deficit in raw causes overproduction of cardial precursor cells in Drosophila at stages 13-14 which is concurrent with the ectopic Dpp activity. This result can be explained because mesodermal overexpression of dpp has shown to promote formation of cardial precursors. Nevertheless, various cardial cells are disappeared in raw mutant embryos at stages 15-16. We hypothesized that loss of cardial cell is resulted from apoptosis in late raw mutants. Indeed, excessive cell death, particularly in dorsal ectoderm and dorsal mesoderm, were observed in raw mutant embryos. Since the distribution of apoptotic cell coincides well with both the spatial and temporal expression domain of ectopic dpp, suggesting that ectopic dpp may induce cardial cell apoptosis in Drosophila. We show that increasing in Dpp activity alone promotes apoptosis in dose-dependent manner. In addition, we show that Dpp induced apoptosis is mediated through dTAK1, as mesodermally expression of a dominant negative dTAK1 suppresses apoptosis of cardial cell in raw mutation embryos. Interestingly, dTAK has shown to activate expression of djnk and dpp. This means that djnk signaling is constitutively activated in mesoderm by ectopic dpp from dorsal ectoderm. We have further demonstrated mesodermal dTAK1 induced apoptosis can be suppressed by expression of dominant negative p53. Since BMP signaling pathway induces apoptosis has also been shown to be mediated through TAK1 in mammals. Thus, the BMP induced apoptosis pathway may be evolutionarily conserved.
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果蠅, 心臟細胞, 細胞凋亡, Raw, Drosophila, JNK, Dpp, apoptosis, TAK1