Evolution of the CNS myelin gene regulatory program

Abstract

Myelin is a specialized subcellular structure that evolved uniquely in vertebrates. A myelinated axon conducts action potentials many times faster than an unmyelinated axon of the same diameter; for the same conduction speed, the unmyelinated axon would need a much larger diameter and volume than its myelinated counterpart. Hence myelin speeds information transfer and saves space, allowing the evolution of a powerful yet portable brain. Myelination in the central nervous system (CNS) is controlled by a gene regulatory program that features a number of master transcriptional regulators including Olig1, Olig2 and Myrf. Olig family genes evolved from a single ancestral gene in non-chordates. Olig2, which executes multiple functions with regard to oligodendrocyte identity and development in vertebrates, might have evolved functional versatility through post-translational modification, especially phosphorylation, as illustrated by its evolutionarily conserved serine/threonine phospho-acceptor sites and its accumulation of serine residues during more recent stages of vertebrate evolution. Olig1, derived from a duplicated copy of Olig2 in early bony fish, is involved in oligodendrocyte development and is critical to remyelination in bony vertebrates, but is lost in birds. The origin of Myrf orthologs might be the result of DNA integration between an invading phage or bacterium and an early protist, producing a fusion protein capable of self-cleavage and DNA binding. Myrf seems to have adopted new functions in early vertebrates - initiation of the CNS myelination program as well as the maintenance of mature oligodendrocyte identity and myelin structure - by developing new ways to interact with DNA motifs specific to myelin genes. This article is part of a Special Issue entitled SI: Myelin Evolution.

Keywords: Evolution; MyRF; Myelin; Olig1; Olig2; Oligodendrocyte; Phylogeny; Transcription factor.

Figure 1

Phylogeny of Olig genes. (A) Olig genes were evolved from a common invertebrate ancestor gene which was duplicated in an early chordate to provide the ancestral genes of Olig1/2/3/4 and Bhlhb4/5. Although we are unsure how many Olig paralogs there are in jawless fish (Agnatha), pre-Olig1 (Olig2-like), Olig2, Olig3, pre-Olig4 (Olig3-like), Bhlhb4 and Bhlhb5 all exist in cartilaginous fish. Olig4 is subsequently lost from all Amniota and Olig1 from Aves. (B) Hypothetical model of Olig gene evolution. A small-scale genomic duplication in the early chordate resulted in the production of ancestors of Olig1/2/3/4 and Bhlhb4/5. After two rounds of whole genome duplication during early vertebrate evolution, accompanied by gene loss, the Olig1/2/3/4 gene ancestor gave rise to Olig2, Olig3 and Olig4 while the Bhlhb4/5 gene ancestor gave rise to Bhlhb4 and Bhlhb5. Meanwhile, a local duplication around the Olig2 locus produced a synteny block containing two Olig2 genes and one of these subsequently underwent recombination with another distantly related bHLH family gene to produce Olig1 (adapted and updated from Li and Richardson, 2009).

Figure 2

Phosphorylation sites of of murine Olig2 (GenBank: NP_058663). Functionally confirmed phosphorylation regions and sites in Olig2 are shown. Akt, CKII and PKA are confirmed kinases that can phosphorylate Olig2 at specific sites. bHLH: basic helix-loop-helix domain; TSM: tripleserine motif; S/T: serine and threonine rich domain.

Figure 3

Phylogeny of Myrf. (A) Structure of murine Myrf protein (GenBank: XP_006526992.1). DBD: DNA binding domain; ICA, intramolecular chaperone auto-processing; TMD: transmembrane domain; SBD, Sox10 binding domain. (B) Myrf phylogenetic tree. Myrf homolog/ortholog sequences were downloaded from NCBI (www.ncbi.nlm.nih.gov) and Ensembl (www.ensembl.org). MEGA6/ClustalW was used to draw the rooted phylogenetic tree (http://www.megasoftware.net/mega.php). Myrf orthologs might result from an invasion event of a phage or bacterium into an early protist resulting in the phage/bacterial DNA (encoding ICA domain) integrating into the protist genome (encoding DBD/Ndt80p domain). In invertebrates, two Myrf homologs evolved simultaneously; in vertebrates, these two Myrf homologs diverged to form Myrf and Myrfl branches. Hs: Homo sapiens; Mm: Mus musculus; Rn: Rattus norvegicus (brown rat); Gg: Gallus gallus (chicken); Ac: Anolis carolinensis (Carolina anole, a lizard); Xt: Xenopus tropicalis (clawed frog); Dr: Danio rerio (zebrafish); Cm: Callorhinchus milii (elephant shark or chimera); Ci: Ciona intestinalis (sea squirt, an ascidian) Cf: Camponotus floridanus (Florida carpenter ant); Sc: Saccharomyces cerevisiae (brewers' yeast); Ce: Caenorhabditis elegans (a nematode worm); Df: Dictyostelium fasciculatum (slime mould); Mb: Monosiga brevicollis (a choanoflagellate, close relative of metazoans); Bb: Bdellovibrio bacteriovorus (a motile gram-negative bacterium that invades and parasitizes other bacteria); CWSAFP: cell wall surface anchor family protein; DTFP: distal tail fibre protein.