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.