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First published online 9 August 2006
doi: 10.1242/dev.02501

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Transcriptional control of midbrain dopaminergic neuron development

Division of Developmental Neurobiology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.

View larger version (28K): [in a new window]   Fig. 1. Dopaminergic neurons in the CNS. Schematic illustrating the location of Th+ neurons, corresponding to A8-A15 groups, in mouse brains ranging from E12.5-E14.5. The DA groups (light blue areas) are depicted in relation to the neuromeric map [subdivision into transeverse segments, see Puelles and Rubenstein (Puelles and Rubenstein, 2003)] and the alar (dorsal) and basal (ventral) plate subdivision. This figure is adapted, with permission, from Marin et al. (Marin et al., 2005). A16 and A17 groups are not shown. cer, cerebellum; d, dorsal; dm, dorsomedial; I-r1, isthmic region; lge, lateral ganglionic emincence; m, mamillary body; Mb, midbrain; mge, medial ganglionic eminence; ob, olfactory bulb; or; optic recess; p, prosomere; sP, secondary prosencephalon.

View larger version (58K): [in a new window]   Fig. 2. Molecularly distinct DA cell populations in the mouse ventral midbrain. (A, part a) An E12.5 mouse embryo. The black line marks the plane of section shown in the image to the right. (A, part b) An enlarged view of the ventral midbrain (square box in A, part a), illustrating the position occupied by mitotic progenitors, immature and mature postmitotic neurons of the mDA lineage. (B) The sequential timing of transcription factor activation in mDA progenitors. The curved arrow indicates cycling cells. (C) The timing of expression of transcription factors in mDA progenitors (not in subsequent steps of the lineage) are shown. Dotted lines indicate that the precise timing of expression shutdown has not been determined. Images in A, part a, and A, part b are courtesy of the Ang Laboratory.

View larger version (12K): [in a new window]   Fig. 3. Model of mDA neuron specification. Shh induces Lmx1a and X (an unknown transcription factor) in mDA progenitors. Based on the timing of induction of endogenous Lmx1a expression compared with Shh expression, the induction of Lmx1a may be indirect. Lmx1a and X then act cooperatively to specify immature mDA neurons. Lmx1a in turn activates Msx1, which induces Ngn2. Ngn2 promotes neuronal differentiation and, perhaps, also the subtype specification of immature mDA neurons. In addition, Msx1 is required and is sufficient for the suppression of Nkx6.1 expression in DA progenitors. Dotted arrows indicate hypothetical functions that remain to be proven. This model is modified, with permission, from Andersson et al. (Andersson et al., 2006b).

View larger version (54K): [in a new window]   Fig. 4. Ngn2 is required for Th+ DA neuron generation, and Mash1 partially compensates for Ngn2 function in the ventral midbrain. Coronal sections showing the expression of Th in DA neurons in the ventral midbrain of (A) wild-type and (B-D) mutant E14.5 mouse embryos. A severe reduction in Th+ DA neuron number in (B) Ngn2-/- and in (C) Ngn2-/-;Mash1-/- mutant embryos is observed, which is not evident in (D) Mash1-/- embryos, which have wild-type numbers of Th+ DA neurons. (E) Partial rescue in the number of Th+ DA neurons in Ngn2KIMash1/KIMash1 (Ngn2KIM1/KIM1) embryos. Modified, with permission, from Kele et al. (Kele et al., 2006).

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