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First published online 26 September 2007
doi: 10.1242/dev.006379

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Spatial and temporal specification of neural fates by transcription factor codes

National Institute for Medical Research, The Ridgeway, Mill Hill, NW7 1AA London, UK.

View larger version (48K): [in this window] [in a new window]   Fig. 1. Sequential generation of different classes of neurons and glia in different domains of the ventral spinal cord. (A) Progenitor domains in the ventral part of the mouse embryonic spinal cord. The vertical axis represents the dorsoventral axis of the spinal cord, the horizontal axis represents developmental time. (B) A cross-section of a mouse embryonic spinal cord (dorsal, top), indicating the position of the progenitor domains shown in A. Progenitor domains shown in A and B are: p0-p2, which generate sequentially V0-V2 interneurons, oligodendrocytes and astrocytes; pMN, which generates sequentially motor neurons (MNs), oligodendrocytes and astrocytes; p3, which generates V3 interneurons, oligodendrocytes and astrocytes. In the ventral spinal cord, oligodendrocyte progenitors (orange) are generated from the pMN and p3 domains and also from the p0 and p1 domains (Fogarty et al., 2005). Patterning proteins (see Box 2), including the homeodomain (HD) proteins Pax6 and Nkx2.2, and the basic helix-loop-helix (bHLH) protein Olig2, which establish the progenitor domains, are initially coexpressed with the inhibitory HLH proteins Id and Hes in uncommitted progenitor cells (grey). The induction of the proneural proteins Ngn2 and Mash1 in progenitors promotes neurogenesis (blue), whereas the induction of Mash1, the maintenance of Olig2 and Nkx2.2 and the downregulation of Pax6 promote oligodendrogenesis (orange), and the downregulation of patterning proteins and the maintenance of inhibitory HLH proteins promote astrogenesis (pink). pD, progenitor domain for dorsal neurons. See text and Sugimori et al. (Sugimori et al., 2007) for further details.

View larger version (36K): [in this window] [in a new window]   Fig. 2. Distinct and overlapping functions of homeodomain proteins and bHLH proteins in neural development. (A) Different families of transcription factors are expressed during sequential phases of neural development. Patterning proteins are expressed early in neural development. Pax6 is then downregulated when progenitor cells become postmitotic. Olig2 expression is maintained in oligodendrocyte progenitors but is downregulated in postmitotic neurons (thinner bar), while Nkx2.2 expression is maintained in both neurons and oligodendrocyte progenitors. Progenitor proteins, such as Lhx3, are induced in mitotic progenitors after the onset of patterning protein expression and remain expressed in postmitotic neurons. Proneural protein expression is induced in subsets of progenitor cells after spatial patterning. Progenitors that express proneural proteins undergo cell type selection and initiate neuronal subtype specification, rapidly followed by cell cycle exit. Proneural protein expression is then switched off in most newborn neurons. Mash1 expression is maintained transiently in oligodendrocyte progenitors (represented by a thinner bar). Neuronal protein expression is induced in progenitor cells following their cell cycle exit. (B) The differentiation of multipotent progenitor cells into specific classes of postmitotic neurons and glia involves transcriptional cascades in which patterning proteins induce proneural proteins, which in turn induce, often directly, neuronal homeodomain proteins (thin arrows). These factors regulate different phases of neural development (thick arrows; see text). Subtype specification is initiated in dividing progenitors coordinately by progenitor proteins and proneural proteins and further promoted by neuronal proteins after cell cycle exit. (C) The molecular mechanisms that underlie the synergistic activity of patterning/progenitor proteins and proneural proteins are largely unknown and could include: (a) indirect interactions through regulation of distinct target genes (e.g. Olig2 and Ngn2) (Mizuguchi et al., 2001; Novitch et al., 2001); (b) binding to distinct sites in the promoter of a common target gene and synergistically activating target gene transcription [e.g. Isl1, Lhx3, Ngn2 and NeuroM (Neurod4)] (Lee and Pfaff, 2003); (c) Cooperative binding of the progenitor protein and the proneural protein to adjacent sites in the promoter of a common target [e.g. Mash1 and Brn2 (also known as Pou3f2)] (Castro et al., 2006). White boxes represent transcription factor binding sites.

View larger version (67K): [in this window] [in a new window]   Fig. 3. Proneural proteins control multiple cellular processes and activate multiple target genes during neurogenesis. Proneural proteins control many aspects of neurogenesis and some of their targets have been identified. (A) Proneural proteins suppress the neural stem cell programme by interfering with the activity of SoxB1 genes (see text); they select neuronal progenitors by directly activating Notch ligands and suppress astrogenesis by interfering with SMAD and STAT signalling (see text). (B) Different proneural proteins specify different neuronal subtype identities by directly activating HD protein-encoding genes, such as Hb9 (Lee and Pfaff, 2003), Dlx1/2 (Poitras et al., 2007) and Mbh1 (also known as Barhl2) (Saba et al., 2005). (C) Proneural proteins also induce the expression of transcription factors that promote neuronal differentiation, including bHLH proteins, T-box proteins and Sox proteins (see text). In addition to regulating transcription factors involved in cell fate specification, proneural proteins also regulate genes that control later steps in the neurogenic programme, such as cell cycle arrest, neuronal differentiation and migration (Farah et al., 2000; Castro et al., 2006; Ge et al., 2006). Some of these genes (e.g. Fbxw7 and doublecortin-like kinase) are regulated cooperatively by the proneural protein Mash1 and the POU HD proteins Brn1 (also known as Pou3f3) and Brn2 (Castro et al., 2006). Tbr2 (Eomes); Dcamkl1 (Dclk1).

View larger version (68K): [in this window] [in a new window]   Fig. 4. The combinatorial activity of patterning proteins and proneural proteins promotes neural cell type commitment. The combinatorial activities of patterning proteins (vertical axis) and of proneural proteins and inhibitory HLH proteins (horizontal axis) in the commitment of progenitor cells to neuronal (N), oligodendroglial (O) or astroglial (A) fates are shown as entries on a matrix. These results were obtained by overexpressing combinations of factors in neural stem cell population cultures derived from rat embryonic spinal cord. The effect of particular transcription factor combinations on the generation of the primary neural cell types is represented by `+' for significant induction, `-' for significant repression and `0' for no activity. See text and Sugimori et al. (Sugimori et al., 2007) for details.

View larger version (42K): [in this window] [in a new window]   Fig. 5. Model of neuronal subtype specification in the retina by combinations of HD and bHLH proteins. Different combinations of bHLH proteins (purple) and HD proteins (red) are expressed by the different classes of neurons and glia in the retina. From mouse mutant analyses and from coexpression of HD proteins and bHLH proteins in mouse retinal explants, Hatakeyama and Kageyama have proposed that the combinatorial activity of different HD and bHLH proteins determines the fate of retinal cells. See text and Hatakeyama and Kageyama (Hatakeyama and Kageyama, 2004) for details. NeuroD (Neurod1).