Involvement of the Olig2 transcriptional factor in the development of the ventral forebrain.

In the developing mammalian central nervous system, the basal forebrain produces various kinds of neurons as well as glial cells. It is thought that oligodendrocyte precursors and motoneurons develop from cells positive for Olig2, a basic helix-loop-helix transcriptional factor, but astrocytes develop from Olig2 negative cells. First, she examined whether astrocytes develop from Olig2 positive cells. The progenies of the cells expressing Olig2 were traced using 4-hydroxytamoxifen-induced Cre-mediated recombination. Olig2 lineage cells expressed PDGFRα (oligodendrocyte precursor marker), MAP2 (neuronal marker) and GFAP (astrocyte marker). This result suggest that Olig2 positive cells differentiate not only to OLPs but also to neurons and astrocytes in the brain for the first time. Zhou and Anderson (2002) showed that astrocyte number increased in the spinal cord of the Olig1/Olig2 double mutant mouse. Thus Olig2 is not directly involved in and is dispensable for the differentiation of ashocyte. In the spinal cord, Olig2-expressing cells generate OLPs and motoneurons. However, the kind of the neuron developed from Olig2-expressing cells in the brain is not known. The VZ of the basal forebrain can be regarded as a main source of subpallial cholinergic neurons. Next I examined involvement of Olig2 in the cholinergic differentiation, since areas presumed to be the sites of cholinergic neuron origin were roughly demarcated by Olig2 expression, which includes the medial ganglionic eminence, septal area, and anterior entopeduncular/preoptic area. She used choline acetyltransferase (ChAT) as a marker of cholinergic neuron. A limited number of ChAT expressing cells in the E18.5 forebrain were also labeled with Olig2. In addition, when the Olig2-expressing cells at E12.5 were permanently modified to express the lacZ gene by tamoxifen-induced Cre-mediated recombination, a small number of cells were double positive for ChAT and X-gal. Therefore, some of the Olig2 expressing cells differentiate into cholinergic neurons in the basal forebrain. She counted ChAT positive cells number in the Olig2 deficient and wild type mice brains. The ChAT positive cell number was reduced to 60 % in the Olig2 knockout mouse forebrain. Cleaved caspase-3 appears in many cases of cell death in the developing brain. The number of cleaved caspase-3 positive cell number hardly changed between wild and Olig2 deficient mice. Therefore, accelerated apoptosis was not likely to be the cause for the decreased cell number in the Olig2 deficient basal forebrain. Nkx2.1, Mash1 and Lhx8 are involved in the development of cholinergic neuron in the forebrain (Zhao et al., 2003; Mori et al., 2004). To elucidate the relationship between Olig2 and other transcriptional factors involved in the differentiation of cholinergic neuron, she examined expression pattern of Nkx2.1, Mash1, and Lhx8 in the E12.5 basal forebrain. Transcription factors seemed to be expressed normally in the Olig2 deficient mouse brains. However, in the Mash1 deficient mouse, Olig2 expression was weakened in the VZ of basal forebrain at E11.5 and E15.5. The present study provides first and direct evidence for involvement of the Olig2 gene in the cholinergic differentiation in the basal forebrain. It is speculated that Olig2 acts down stream of Nkx2.1 and Mash1, and possibly represents the Lhx8-independent pathway. Mufson, E. J., S. D. Ginsberg, M. D. Ikonomovic and S. T. DeKosky (2003). J Chem Neuroanat 26(4): 233-42. Zhao, Y., O. Marin, E. Hermesz, A. Powell, N. Flames, M. Palkovits, J. L. Rubenstein and H. Westphal (2003). "Proc Nail Acad Sci U S A 100(15): 9005-10.Zhou, Q. and D. J. Anderson (2002). Cell 109(l): 61-73