Abstract
The transforming growth factor-βs (TGF-βs) are multifunctional cytokines capable of regulating a wide range of cellular behaviors and play a key role in maintaining the homeostasis of the immune system. The TGF-β subfamily, which is only present in deuterostomes, expands from a single gene in invertebrates to multiple members in jawed vertebrates. However, the evolutionary processes of the TGF-β subfamily in vertebrates still lack sufficient elucidation. In this study, the TGF-β homologs are identified at the genome-wide level in the reissner lamprey (Lethenteron reissneri), the sea lamprey (Petromyzon marinus), and the Japanese lamprey (Lampetra japonica), which are the extant representatives of jawless vertebrates with a history of more than 350 million years. The molecular evolutionary analyses reveal that the lamprey TGF-β subfamily contains two members representing ancestors of TGF-β2 and 3 in vertebrates, respectively, but TGF-β1 is absent. The transcriptional expression patterns show that the lamprey TGF-β2 may play a central regulatory role in the innate immune response of the lamprey since it exhibits a more rapid and significant upregulation of expression than TGF-β3 during lipopolysaccharide stimuli. The incorporation of BrdU assay reveals that the lamprey TGF-β2 recombinant protein exerts the bipolar regulation on the proliferation of the supraneural myeloid body cells (SMB cells) in the quiescent and LPS-activated state, while plays an inhibitory role in the proliferation of quiescent and activated leukocytes in lampreys. Furthermore, caspase-3/7 activity analysis indicates that the lamprey TGF-β2 protects SMB cells from apoptosis after serum deprivation, in contrast to promoting apoptosis of leukocytes. Our composite results offer valuable clues to the origin and evolution of the TGF-β subfamily and imply that TGF-βs are among the most ancestral immune regulators in vertebrates.
Highlights
The transforming growth factor-b (TGF-b) superfamily is a large family of multifunctional cytokines containing many members
Based on phylogenetic analysis and sequence homology comparison, we further found that these sequences represented two classes of TGF-b subfamily members
The TGF-b2 gene had two homologous gene copies, TGF-b2A and TGF-b2B, in both reissner lamprey and sea lamprey, respectively, and only one TGF-b2 homologous gene was found in Japanese lamprey
Summary
The transforming growth factor-b (TGF-b) superfamily is a large family of multifunctional cytokines containing many members. The first members of the TGF-b superfamily to emerge were BMPs/GDFs, which subsequently differentiated into Activins/Inhibins, while the ‘ture’ TGF-b subfamily emerged later and is only present in deuterostomes [3, 4]. Both the two lower phyla of deuterostomes, including sea urchins (Echinodermata) and acorn worms (Hemichordata), contain a single true TGF-b homolog, while sea squirts (Urochordata) and amphioxus (Cephalochordata) in the Chordata contain a single TGF-b homolog. The origin and evolution of all members of the TGF-b subfamily in other representative species have remained unclear to date due to a lack of high-quality genomic data, except for studies in humans and other model animals. Highquality sequencing of the genome of one of the extant representatives of the jawless vertebrates, the reissner lamprey (Lethenteron reissneri), has been completed [7], offering new possibilities for filling key links in the evolution of TGF-bs
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