The unicellular ancestry of the proto-oncogene Myc
The origin of metazoans required the evolution of mechanisms of cell-cell adhesion, coordination and communication among neighboring cells, and the establishment of differentiated cell types. Did the molecular building blocks of metazoan multicellularity exist in their single celled ancestors, or are they unique metazoan innovations? To address this question we sequenced and analyzed the genome of the unicellular marine choanoflagellate Monosiga brevicollis. Choanoflagellates, a phylum of flagellated unicellular and colonial eukaryotes found in diverse aqueous habitats around the globe, are among the closest living relatives of metazoans.
The roughly 46 million base pair genome of M. brevicollis contains approximately 9,200 unexpectedly intron-rich genes, including a number of genes that encode cell adhesion and signaling protein domains that are otherwise restricted to metazoans. The physical linkages among these domains often differ between M. brevicollis and metazoans suggesting that abundant domain shuffling followed the separation and subsequent diversification of the choanoflagellate and metazoan lineages. Metazoans also have a richer diversity of transcription factors than does M. brevicollis, indicating that the evolution of early metazoans may have involved an increase in the sophistication of transcriptional regulation. Nonetheless, a few metazoan-type transcription factors were identified in M. brevicollis: members of the p53, Myc, and Sox/TCF transcription factor families.
Myc is a developmentally critical transcription factor that plays roles in the most fundamental of cellular processes: cell growth, proliferation, and death. Investigating the function of Myc in choanoflagellates promises to delineate the role of Myc before the origin of animals and may inform how the strict regulation of cell life and death in metazoans arose from a unicellular context. Here, we demonstrate M. brevicollis Myc heterodimerizes with M. brevicollis MAX and localizes to the nucleus and cytoplasm of choanoflagellate cells in varying intensity. We further show that the tyrosine kinase (TK) inhibitor genistein reduces the expression of MbMyc, suggesting that TK signaling regulates MbMyc. Because metazoans Mycs are also known to be regulated by TK signaling, we hypothesize that an emergent network of TK signaling and transcriptional regulation was present in the unicellular ancestor of animals.