A Turn of the Helix: Preventing the Glial Fate

Abstract

Multipotent progenitor cells undergo progressive restriction in potential to give rise to either a neuronal or glial lineage, but at what step in this process do the bHLH factors function to contribute to the lineage restriction? Nieto et al. (2001)xNieto, M, Schuurmans, C, Britz, O, and Guillemot, F. Neuron. 2001; 29: 401–413Abstract | Full Text | Full Text PDF | PubMed | Scopus (369)See all References)Nieto et al. (2001) found that ngn2 is not expressed in multipotent progenitors, but surprisingly is expressed in both neural restricted and glial restricted progenitors. Ngn2 may therefore not be regulating the choice of multipotent progenitors to become restricted in their potential to either the neuronal or glial lineage, but may instead act to reinforce this decision. The expression of ngn1 has not been described in this level of detail, so it is not clear whether ngn1 is also acting in separate precursors for neurons and glia. If so, then additional signals may be necessary to initially distinguish the neural lineage from the glial lineage. What would be the function of the neurogenins in the glial-restricted precursors? One possibility is that proneural bHLH factors act in glial-restricted precursors to limit their complete differentiation to mature astrocytes, perhaps by inhibiting the expression of glial-specific genes, such as GFAP. Alternatively, proneural bHLH factors may play an additional role in regulating the astrocyte versus oligodendrocyte fate decision. In OPCs, Wang et al. (2001)xWang, S, Sdrulla, A, Johnson, J.E, Yokota, Y, and Barres, B.A. Neuron. 2001; 29: 603–614Abstract | Full Text | Full Text PDF | PubMed | Scopus (165)See all References)Wang et al. (2001) found that Mash1 is expressed but that loss of Mash1 expression had no effect on the proliferation or differentiation of these cells. It is possible that other bHLH factors expressed in OPCs, such as olg1 or olg2 (Lu et al. 2000xLu, Q.R, Yuk, D, Alberta, J.A, Zhu, Z, Pawlitzky, I, Chan, J, McMahon, A.P, Stiles, C.D, and Rowitch, D.H. Neuron. 2000; 25: 317–329Abstract | Full Text | Full Text PDF | PubMedSee all References, Zhou et al. 2000xZhou, Q, Wang, S, and Anderson, D.J. Neuron. 2000; 25: 331–343Abstract | Full Text | Full Text PDF | PubMedSee all References), can compensate for the loss of Mash1 expression. At this time the function of proneural bHLH factors in the glial restricted lineage remains to be determined.Together, the studies highlighted above provide us with unprecedented insight into the molecular mechanisms regulating the neuronal/glial fate choice during development and demonstrate that bHLH factor expression can be an important contributor to this decision. Will these advances enhance our ability to use neural stem cells to therapeutically treat nervous system disease and injury? There is no doubt that defining the molecular mechanisms governing stem cell differentiation will make this much more likely. Sun et al. (2001)xSun, Y, Nadal-Vicens, M, Misono, S, Lin, M.Z, Zubiaga, A, Hua, X, Fan, G, and Greenberg, M.E. Cell. 2001; 104: 365–376Abstract | Full Text | Full Text PDF | PubMed | Scopus (509)See all References)Sun et al. (2001) have suggested a therapeutic application for their work by stating that manipulation of proneural bHLH factor expression could be used to enhance the probability that neural stem cells differentiate into neurons rather than glia in vivo. However, sustained expression of bHLH factors in differentiated neurons in vivo eventually causes neuronal cell death (Cai et al., 2000xCai, L, Morrow, E.M, and Cepko, C.L. Development. 2000; 127: 3021–3030PubMedSee all References)(Cai et al., 2000), suggesting caution about this approach. In the end, we must still make the leap from controlling the differentiation of these cells under defined conditions in culture, and understanding how these events happen in the complex cellular environment encountered by these cells in vivo. Nevertheless, the recent studies highlighted above are significant for providing an illuminating glimpse into the mechanisms governing the neuronal/glial fate decision during development.