Cyclostome and chondrichthyan adrenomedullins reveal ancestral features of the adrenomedullin family

The adrenomedullin (AM) family is a newly identified group of regulatory peptides involved in various aspects of homeostasis. Different forms of AMs are the result of genome duplication during vertebrate evolution, but nothing is known about the AM genes before divergence of bony fish. In the present study, we identified novel AM genes in cyclostomes (a hagfish and two lamprey species) and chondrichthyes (a holocephalan and two elasmobranch species). The AM of cyclostomes possessed features of both AM1 and AM2, with gene structure and overall precursor sequence more similar to AM1 of teleosts and tetrapods but mature sequence more similar to AM2. A sequence reminiscent of proAM N-terminal 20 peptide (PAMP), another bioactive peptide present in the prosegment of AM1 precursors, exists in the lamprey AM precursor. An AM gene with both AM1 and AM2 characteristics was also found in chondrichthyes, and an additional AM5-like gene was detected in Squalus acanthias. The hybrid-type AM gene from cyclostomes and chondrichthyes was expressed ubiquitously in all tissues examined including the skeletal muscle, while the Squalus AM5-like gene transcripts were detected more specifically in the liver. Taken together, the ancestral gene of the AM family appears to possess both AM1 and AM2 characteristics as observed in the lamprey AM gene, and the general structure including PAMP was retained by the extant AM1 genes, but the mature sequence was retained by the extant AM2 genes.