Induction of the mammalian node requires Arkadia function in the extraembryonic lineages

The early mammalian embryo is patterned by signals emanating from extraembr yonic and embryonic signalling centres, most notably the anterior visceral endoderm (AVE) and the node, respectively(1). The AVE is responsible for an terior development, whereas further axis specification depends on the node, the equivalent of Spemann's organizer(2,3). Formation of the node, at the anterior primitive streak, depends on expression of the transcription facto r HNF3 beta (ref. 4). However, both the source and the nature of the signal s responsible for inducing the node have been unknown. Here we describe a r ecessive lethal mutation, arkadia, generated using gene-trap mutagenesis. M utant embryos establish an AVE but fail to maintain anterior embryonic stru ctures and lack a node. The mutation has disrupted the Arkadia gene, which encodes a putative intracellular protein containing a RING domain. Arkadia is essential for HNF3 beta expression in the anterior primitive streak. Ana lysis with chimaeras, however, shows that Arkadia functions within extraemb ryonic tissues, revealing that these are required to induce the node. Furth ermore, our experiments show that Arkadia interacts genetically with the tr ansforming growth factor (TGF)beta -like factor Nodal(5-7), implying that N odal mediates the function of Arkadia in node induction.