Editors' ChoiceDevelopment

BMP15 Mutants Lose Their Heads

Science Signaling  22 Sep 2009:
Vol. 2, Issue 89, pp. ec316
DOI: 10.1126/scisignal.289ec316

Di Pasquale and Brivanlou present an exploration of the embryological function of bone morphogenetic protein 15 (BMP15) in Xenopus that yields insights into its mechanism of action and roles in embryogenesis and also allows the authors to suggest a possible new interpretation of why its mutation in adult human females leads to ovarian failure. BMP15 is a member of the transforming growth factor–β (TGFβ) family and has structural features shared by family members that inhibit TGFβ signaling. Injection of Xenopus embryos with RNA encoding BMP15 caused formation of a secondary head structure, and treatment of embryo explants with BMP15 directly caused formation of neural tissue. These effects appeared to result from inhibitory effects on signaling through TGFβ signaling pathways. BMP15 inhibited the ability of BMP4 to promote formation of epidermis in embryo explants and inhibited BMP4-dependent increase in transcription from a BMP-responsive element. Interaction of tagged forms of BMP15 and BMP4 could be detected when expressed in embryos, suggesting a possible mechanism for the antagonism. BMP15 also appeared to be necessary for head formation in embryos, because expression of a dominant-negative mutant caused formation of embryos without heads. BMP15 could also inhibit Wnt signaling in embryos, a property shared with some other TGFβ pathway inhibitors. The authors discuss how, when morphogen gradients establish cell fates in the embryo, BMP15 might function to prevent inappropriate spread of TGFβ and Wnt signals to the animal pole and to limit BMP4 signals to allow formation of neural structures. If BMP15 has similar inhibitory effects in granulosa cells of the ovary, the mechanisms leading to premature infertility in women expressing the dominant-negative form of BMP15 may be rather different from the loss of downstream TGFβ signaling considered previously.

E. Di Pasquale, A. H. Brivanlou, Bone morphogenetic protein 15 (BMP15) acts as a BMP and Wnt inhibitor during early embryogenesis. J. Biol. Chem. 284, 26127–26136 (2009). [Abstract] [Full Text]