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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.
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