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Foxd4 is essential for establishing neural cell fate and for neuronal differentiation.
Sherman JH
,
Karpinski BA
,
Fralish MS
,
Cappuzzo JM
,
Dhindsa DS
,
Thal AG
,
Moody SA
,
LaMantia AS
,
Maynard TM
.
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Many molecular factors required for later stages of neuronal differentiation have been identified; however, much less is known about the early events that regulate the initial establishment of the neuroectoderm. We have used an in vitro embryonic stem cell (ESC) differentiation model to investigate early events of neuronal differentiation and to define the role of mouse Foxd4, an ortholog of a forkhead-family transcription factor central to Xenopus neural plate/neuroectodermal precursor development. We found that Foxd4 is a necessary regulator of the transition from pluripotent ESC to neuroectodermal stem cell, and its expression is necessary for neuronal differentiation. Mouse Foxd4 expression is not only limited to the neural plate but it is also expressed and apparently functions to regulate neurogenesis in the olfactory placode. These in vitro results suggest that mouse Foxd4 has a similar function to its Xenopus ortholog; this was confirmed by successfully substituting murine Foxd4 for its amphibian counterpart in overexpression experiments. Thus, Foxd4 appears to regulate the initial steps in establishing neuroectodermal precursors during initial development of the nervous system.
FIGURE 6 Mouse Foxd4 has a similar ability as frog foxd4l1 to
regulate expression of neuroectodermal genes. (a) Xenopus 16-cell
epidermal progenitors (blastomere V1.1) were microinjected with
indicated mRNAs and embryos examined at stages 10.5–11.5 for
the presence of the clonal progeny of the injected cell (pink nuclear
labeling) and for mRNA expression by in situ hybridization (diffuse
blue labeling). As an example, gmnn was ectopically induced in the
ventralepidermis by mouse Foxd4 but not by the lineage tracer
(nbgal). (b) High magnification image of injected embryos. Ectopic
expression of either frog foxd4l1 or mouse Foxd4 leads to induction
of gmnn, zic2, and sox11 expression (blue label) in the ventralepidermis
within the injected cell clone (pink nuclei). (c) The percentage
of embryos that show ectopic induction of each neural gene in
the ventralepidermis after injection of frog foxd4l1 (green bars) or
mouse Foxd4 (blue bars; n for each experiment noted on graph). (d)
There is a high degree of homology between frog foxd4l1 and
mouse Foxd4, particularly within the N-terminal “acidic blob†(AB)
domain and the C-terminal Eh1 domain, which have previously
been identified as key activator and repressor domains in frog
foxd4l1. (e) Xenopus 16-cell neural ectoderm progenitors (blastomere
D1.1) were microinjected with indicated mRNAs and examined
at stages 11.5–12.5 as above. As examples, gmnn expression
in the neural ectoderm was increased by mouse Foxd4 but not by
the lineage tracer (nbgal), and sox11 expression was repressed
(arrows). (f) High magnification image of injected embryos, illustrating
modulation of expression in injected clones. Injection of either
frog foxd4l1 or mouse Foxd4 lead to increased expression of gmnn
and zic2 within the injected clone (asterisk), relative to the level in
neighboring uninjected cells that are also in the neural ectoderm
(e). Similarly, injection of either frog foxd4l1 or mouse Foxd4 lead
to decreased expression of sox11 and zic1 relative to adjacent
uninjected neural ectoderm (e). (g) The percentage of embryos that
show either increased expression (left) or decreased expression
(right) of each neural gene in the neural ectoderm after injection of
frog foxd4l1 (green bars) or mouse Foxd4 (blue bars). The number
of replicates for each experiment is noted within each bar on the
graphs (c, g)
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