Human Dullard has shown that the protein has two membrane spanning regions. One end is the N-terminal end, which helps localize the protein to the nuclear envelope. Dullard dephosphorylates the mammalian phospatidic acid phosphatase, lipin. Dullard participates in a unique phosphatase cascade regulating nuclear membrane biogenesis, and that this cascade is conserved from yeast to mammals. There is belief that Dullard may have other targets that is not only associated with the nuclear envelope. In recent studies, dullard interacts with BMP type 1 to inhibit dependent phosphorylation. This can conclude that it is a potential source for regulating the level of BMP signaling and can affect germ cell specification.
The late onset of the phenotype was unexpected, considering the importance of BMP activity during embryonic kidney development. Proper levels of BMP4 and BMP7 are required for kidney formation, and deletion of BMP modulators, such as Gremlin and Crossveinless, results in kidney agenesis or hypoplasia at birth16,23. By contrast, the Dullard mutant mice exhibited no obvious defects until birth, but started to lose their nephrons at 2 weeks after birth, which is different from all phenotypes in mice lacking other BMP-related molecules. It is possible that other BMP modulators could compensate for the Dullard deletion until birth, but not after birth. Alternatively, Dullard could fine-tune the BMP signalling in specialized biological settings instead of being a general BMP signalling inhibitor. Although our data for C3H10T1/2 and ES cells suggest the former possibility, the relationship between Dullard and BMP signalling in vivo remains to be elucidated. Nevertheless, it is interesting that BMP signalling should be suppressed to an appropriate level for postnatal nephron maintenance. Since Bmp2 and Bmp7 decreased after birth, while Bmp4 remained constant, in both the control and mutant mice, the enhancement of BMP signalling in the Dullard mutant mice could arise through decreased degradation of BMP receptors, as proposed previously10. Although we did not detect significant increases in the BMP receptor levels in the Dullard mutant kidneys at P7 (Supplementary Fig. S6b), it is still possible that slightly increased amounts of the receptors, which were undetectable by western blot analyses, could lead to the increased BMP signalling, because of the high turnover rate of the receptors. Alternatively, Dullard could negatively regulate BMP signalling though Lipin, a phosphatidate phosphatase24,25. Dullard is involved in the regulation of nuclear membrane biogenesis by dephosphorylating Lipin in cultured cells24. It was also reported that Drosophila dullard functions via lipin to regulate the production of diacylglycerol from phosphatidic acid and maintains the proper lipid composition of the nuclear membrane at nuclear pore complexes25. Thus, impairment of this process could affect the nuclear translocation of phosphorylated Smad proteins11.
As with Heyst, so with Horgan: Life comes to get him; nudges him, reluctant and unwilling, into the game (baseball, here) of life. Perhaps, in a fable, we can allow a metamorphosis from dullard to sage without any character development, for the Horgan of the closing pages is quite unlike the dull figure we meet as the novel opens.
Bone morphogenetic protein (BMP) signaling is essential for neurogenesis and bone formation. Dullard phosphatase functions as a negative regulator of BMP signaling by promoting the dephosphorylation or degradation of BMP receptors. In contrast, dullard regulates nuclear membrane biogenesis. This report aims to characterize dullard and determine the role played by it in cellular signaling. 041b061a72