Editors' ChoiceDevelopmental Biology

Mutually Exclusive Transcription

Science Signaling  28 Aug 2012:
Vol. 5, Issue 239, pp. ec226
DOI: 10.1126/scisignal.2003531

Signaling by the bone morphogenetic protein (BMP) class of transforming growth factor–β (TGF-β) ligands directs the establishment of embryonic dorsoventral (DV) polarity in most animals. In many vertebrates (mammals excluded), the BMP ligand antidorsalizing morphogenetic protein (Admp) opposes the actions of BMP4 and BMP7 to specify the DV axis. In the sea squirt Ciona intestinalis, opposing activities of Admp and a BMP orthologous to vertebrate BMP2 and BMP4 (BMP2/4) direct DV axis formation, with Bmp2/4 expressed in the ventral epidermis and Admp in the lateral epidermis and dorsal ectoderm. Imai et al. report that the gene encoding the Ciona homolog of the Xenopus TGF-β ligand Pinhead is located adjacent to Admp and is expressed in the ventral epidermis in a domain that overlapped that of Bmp2/4 but did not overlap the Admp expression domain. Both Admp and BMP2/4 were required for Pinhead expression. Pinhead antagonized both BMP2/4 and Admp signaling, as assayed by the expression of ventral and lateral cell fate markers in embryos injected with morpholino oligonucleotides directed against these ligands. In coimmunoprecipitation assays with tagged proteins, Pinhead directly interacted with Admp robustly, but only weakly with BMP2/4. The authors found that the Pinhead and Admp genes were located next to one another and in the same orientation in many invertebrates and nonmammalian vertebrates, suggesting that this arrangement of the genes was important for some aspect of their function. Using fluorescent reporter constructs driven by the cis-regulatory regions of Pinhead and Admp, the authors demonstrated that transcription of these two genes was mutually exclusive. Chromatin conformation capture methods indicated that transcription of Pinhead caused sequestration of the enhancer driving Admp expression. These results suggest a model in which Pinhead suppresses Admp activity in two ways: first indirectly at the transcriptional level by reducing Admp production and then at the protein level through direct interaction.

K. S. Imai, Y. Daido, T. G. Kusakabe, Y. Satou, Cis-acting transcriptional repression establishes a sharp boundary in chordate embryos. Science 337, 964–967 (2012). [Abstract] [Full Text]