Separated at birth? The functional and molecular divergence of OLIG1 and OLIG2

Abstract

The basic helix-loop-helix transcription factors oligodendrocyte transcription factor 1 (OLIG1) and OLIG2 are structurally similar and, to a first approximation, coordinately expressed in the developing CNS and postnatal brain. Despite these similarities, it was apparent from early on after their discovery that OLIG1 and OLIG2 have non-overlapping developmental functions in patterning, neuron subtype specification and the formation of oligodendrocytes. Here, we summarize more recent insights into the separate roles of these transcription factors in the postnatal brain during repair processes and in neurological disease states, including multiple sclerosis and malignant glioma. We discuss how the unique functions of OLIG1 and OLIG2 may reflect their distinct genetic targets, co-regulator proteins and/or post-translational modifications.

FIG. 1. The developmental roles of OLIG1 and OLIG2

a | Impact of Olig1 and/or Olig2 ablation on spinal cord patterning in mice. The combinatorial interactions of homeodomain proteins organize the ventral spinal cord of developing mouse embryos into five distinct regions, namely the p0, p1, p2, pMN and p3 domains. Different classes of ventral interneurons arise from the p0–p3 domains, whereas motor neurons and oligodendrocytes are derived from progenitors in the pMN domain (see REF. for a review). Knockout of Olig1 has little affect on maintenance of the pMN domain, whereas knockout of Olig2 results in ventral expansion of the p2 domain. Combinatorial knockout leads to the complete disappearance of the pMN domain (see REF. for a review). b | Non-overlapping roles for Olig1 and Olig2 in proliferation and differentiation of neural progenitors. OLIG1 promotes the differentiation of committed oligodendrocyte progenitors, a function that may be even more readily apparent in repair scenarios than in development. By contrast, OLIG2 functions at earlier developmental stages. Initially, OLIG2 acts to oppose cell differentiation and sustains the replication competent state so as to expand the pool of progenitors. At later stages of development, OLIG2 promotes the fate choice decision to form early oligodendrocyte progenitors and certain types of neurons, notably motor neurons in the developing spinal cord. Generally speaking, OLIG2 suppresses the formation of astrocytes, although there may be regional exceptions to this rule and it has been suggested that OLIG2 has a role in reactive gliosis.

FIG. 1. The developmental roles of OLIG1 and OLIG2

a | Impact of Olig1 and/or Olig2 ablation on spinal cord patterning in mice. The combinatorial interactions of homeodomain proteins organize the ventral spinal cord of developing mouse embryos into five distinct regions, namely the p0, p1, p2, pMN and p3 domains. Different classes of ventral interneurons arise from the p0–p3 domains, whereas motor neurons and oligodendrocytes are derived from progenitors in the pMN domain (see REF. for a review). Knockout of Olig1 has little affect on maintenance of the pMN domain, whereas knockout of Olig2 results in ventral expansion of the p2 domain. Combinatorial knockout leads to the complete disappearance of the pMN domain (see REF. for a review). b | Non-overlapping roles for Olig1 and Olig2 in proliferation and differentiation of neural progenitors. OLIG1 promotes the differentiation of committed oligodendrocyte progenitors, a function that may be even more readily apparent in repair scenarios than in development. By contrast, OLIG2 functions at earlier developmental stages. Initially, OLIG2 acts to oppose cell differentiation and sustains the replication competent state so as to expand the pool of progenitors. At later stages of development, OLIG2 promotes the fate choice decision to form early oligodendrocyte progenitors and certain types of neurons, notably motor neurons in the developing spinal cord. Generally speaking, OLIG2 suppresses the formation of astrocytes, although there may be regional exceptions to this rule and it has been suggested that OLIG2 has a role in reactive gliosis.

Figure 2. OLIG1 and OLIG2 localization

OLIG1 and OLIG2 (both visualized in red) are both present in the nuclei (blue) of oligodendrocytes and their progenitors at postnatal day (P) 1 in the mouse brain. OLIG2 continues to have a nuclear localization at all developmental stages, whereas OLIG1 is found almost completely in the cytoplasm in the adult mouse brain.

Figure 3. OLIG1 and OLIG2 downstream gene targets

The gene sets regulated by OLIG1 and OLIG2 only partially overlap. a | The number of genes that show upregulated expression in Olig1 and/or Olig2 null neural progenitor cells compared with wild-type neural progenitor cells. b | The number of genes that show down-regulated expression in Olig1 and/or Olig2 null neural progenitor cells compared with wild-type counterparts. The Olig2 data set is taken from REF. , whereas the Olig1 expression profiling data sets (S. Mehta, H. Liu, J. Alberta, E. Huillard, D. Rowitch, C. Stiles, unpublished observations) are available from the NCBI GEO database (GSE39706).

Figure 3. OLIG1 and OLIG2 downstream gene targets

The gene sets regulated by OLIG1 and OLIG2 only partially overlap. a | The number of genes that show upregulated expression in Olig1 and/or Olig2 null neural progenitor cells compared with wild-type neural progenitor cells. b | The number of genes that show down-regulated expression in Olig1 and/or Olig2 null neural progenitor cells compared with wild-type counterparts. The Olig2 data set is taken from REF. , whereas the Olig1 expression profiling data sets (S. Mehta, H. Liu, J. Alberta, E. Huillard, D. Rowitch, C. Stiles, unpublished observations) are available from the NCBI GEO database (GSE39706).

Figure 4. Post-translational modification motifs in OLIG1 and OLIG2

a | Human OLIG2 contains a number of serine phosphorylation sites, which are conserved in mouse OLIG2. The triple serine motif in N terminus of human OLIG2 and Ser147 are entirely conserved in chicken, Xenopus laevis and zebrafish. b | Human OLIG1 contains a serine residue at position 138 that seems to correspond to Ser147 in OLIG2. Protein alignment of OLIG1 orthologues from human, mouse and rat reveals a conserved putative SUMOylation motif close to the basic helix–loop–helix (bHLH) domain (inset).

Figure 4. Post-translational modification motifs in OLIG1 and OLIG2

a | Human OLIG2 contains a number of serine phosphorylation sites, which are conserved in mouse OLIG2. The triple serine motif in N terminus of human OLIG2 and Ser147 are entirely conserved in chicken, Xenopus laevis and zebrafish. b | Human OLIG1 contains a serine residue at position 138 that seems to correspond to Ser147 in OLIG2. Protein alignment of OLIG1 orthologues from human, mouse and rat reveals a conserved putative SUMOylation motif close to the basic helix–loop–helix (bHLH) domain (inset).