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Fig. 6. Wnt1 may control two different steps in the generation of mDA neurons in
vivo. (A) Schematic drawing of a cross section through the mouse
ventral midbrain close to the MHB at E9.5-10.5 showing the overlapping
expression of Shh (black) and Wnt1 (green) in the midbrain FP and BP. Wnt1 is
spared from the ventral midline (medial FP), where only Shh is expressed. Otx2
(yellow) is expressed throughout the midbrain neuroepithelium at this stage,
overlapping with a narrow stripe corresponding to the Nkx2-2 expression domain
(red). Both Wnt1 and Otx2 are engaged in a positive feedback loop controlling
their expression within the ventral midbrain such that secreted Wnt1 protein
induces and/or maintains Otx2 expression in the FP and BP of the
midbrain and vice versa. Otx2 protein is in turn required for repression of
Nkx2-2 within this territory of the neural tube. The mDA progenitor
domain is thus established by this Wnt1-controlled regulatory network during
early neural development. (B) Schematic drawing of a cross-section
through the mouse ventral midbrain close to the MHB at E12.5. The Shh (black)
and Wnt1 (green) expression domains have refined to a narrow area
corresponding to the ventricular and subventricular zone and partly
overlapping with the Otx2-positive (yellow) proliferative neuroepithelium of
the midbrain FP and BP. The Nkx2-2 (red) domain is now restricted to a
wedge-shaped transversal stripe at the alar-basal boundary corresponding to
the region of lowest Otx2 protein levels. At this stage, proliferating mDA
progenitors within the midbrain FP/BP have already generated Th-expressing mDA
precursors. Wnt1 may be required for terminal differentiation of these cells
by inducing expression of Pitx3 (blue). The as yet hypothetical nature of a
direct role of Wnt1 in the generation of mDA neurons is indicated by broken
lines.
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