Wagner Daniel S, Mullins Mary C
Department of Cell and Developmental Biology, University of Pennsylvania Medical School, Philadelphia, PA 19104, USA.
Dev Biol. 2002 May 1;245(1):109-23. doi: 10.1006/dbio.2002.0614.
We analyzed the interactions between mutations in antagonistic BMP pathway signaling components to examine the roles that the antagonists play in regulating BMP signaling activity. The dorsalized mutants swirl/bmp2b, snailhouse/bmp7, lost-a-fin/alk8, and mini fin/tolloid were each analyzed in double mutant combinations with the ventralized mutants chordino/chordin and ogon, whose molecular nature is not known. Similar to the BMP antagonist chordino, we found that the BMP ligand mutants swirl/bmp2b and snailhouse/bmp7 are also epistatic to the putative BMP pathway antagonist, ogon, excluding a class of intracellular antagonists as candidates for ogon. In ogon;mini fin double mutants, we observed a mutual suppression of the ogon and mini fin mutant phenotypes, frequently to a wild type phenotype. Thus, the Tolloid/Mini fin metalloprotease that normally cleaves and inhibits Chordin activity is dispensable, when Ogon antagonism is reduced. These results suggest that Ogon encodes a Tolloid and Chordin-independent antagonistic function. By analyzing genes whose expression is very sensitive to BMP signaling levels, we found that the absence of Ogon or Chordin antagonism did not increase the BMP activity remaining in swirl/bmp2b or hypomorphic snailhouse/bmp7 mutants. These results, together with other studies, suggest that additional molecules or mechanisms are essential in generating the presumptive gastrula BMP activity gradient that patterns the dorsal-ventral axis. Lastly we observed a striking increased penetrance of the swirl/bmp2b dominant dorsalized phenotype, when Chordin function is also absent. Loss of the BMP antagonist Chordin is expected to increase BMP signaling levels in a swirl heterozygote, but instead we observed an apparent decrease in BMP signaling levels and a loss of ventral tail tissue. As has been proposed for the fly orthologue of chordin, short gastrulation, our paradoxical results can be explained by a model whereby Chordin both antagonizes and promotes BMP activity.
我们分析了拮抗BMP信号通路成分中的突变之间的相互作用，以研究拮抗剂在调节BMP信号活性中所起的作用。将背化突变体swirl/bmp2b、snailhouse/bmp7、lost-a-fin/alk8和mini fin/tolloid分别与腹化突变体chordino/chordin和ogon进行双突变组合分析，ogon的分子本质尚不清楚。与BMP拮抗剂chordino类似，我们发现BMP配体突变体swirl/bmp2b和snailhouse/bmp7对于假定的BMP信号通路拮抗剂ogon也是上位性的，排除了一类细胞内拮抗剂作为ogon候选者的可能性。在ogon;mini fin双突变体中，我们观察到ogon和mini fin突变体表型的相互抑制，经常达到野生型表型。因此，当ogon拮抗作用减弱时，正常情况下切割并抑制Chordin活性的Tolloid/Mini fin金属蛋白酶是可有可无的。这些结果表明，ogon编码一种不依赖Tolloid和Chordin的拮抗功能。通过分析其表达对BMP信号水平非常敏感的基因，我们发现缺乏ogon或Chordin拮抗作用并不会增加swirl/bmp2b或低表达的snailhouse/bmp7突变体中剩余的BMP活性。这些结果与其他研究一起表明，额外的分子或机制对于产生确定背腹轴模式的原肠胚BMP活性梯度至关重要。最后，我们观察到当Chordin功能也缺失时，swirl/bmp2b显性背化表型的外显率显著增加。BMP拮抗剂Chordin的缺失预计会增加swirl杂合子中的BMP信号水平，但相反，我们观察到BMP信号水平明显降低以及腹侧尾部组织缺失。正如针对chordin的果蝇同源物short gastrulation所提出的那样，我们的矛盾结果可以通过一个模型来解释，即Chordin既拮抗又促进BMP活性。
