Neurogenin 2 is required for the development of ventral midbrain dopaminergic neurons.
Proneural genes are crucial regulators of neurogenesis and subtype specification in many areas of the nervous system; however, their function in dopaminergic neuron development is unknown. We report that proneural genes have an intricate pattern of expression in the ventricular zone of the ventral midbrain, where mesencephalic dopaminergic neurons are generated. Neurogenin 2 (Ngn2) and Mash1 are expressed in the ventral midline, while Ngn1, Ngn2 and Mash1 are co-localized more laterally in the ventricular zone. Ngn2 is also expressed in an intermediate zone immediately adjacent to the ventricular zone at the ventral midline. To examine the function of these genes, we analyzed mutant mice in which one or two of these genes were deleted (Ngn1, Ngn2 and Mash1) or substituted (Mash1 in the Ngn2 locus). Our results demonstrate that Ngn2 is required for the differentiation of Sox2(+) ventricular zone progenitors into Nurr1(+) postmitotic dopaminergic neuron precursors in the intermediate zone, and that it is also likely to be required for their subsequent differentiation into tyrosine hydroxylase-positive dopaminergic neurons in the marginal zone. Although Mash1 normally has no detectable function in dopaminergic neuron development, it could partially rescue the generation of dopaminergic neuron precursors in the absence of Ngn2. These results demonstrate that Ngn2 is uniquely required for the development of midbrain dopaminergic neurons.
Kele
Julianna
J
Laboratory of Molecular Neurobiology, MBB, Karolinska Institutet, Retzius building A1, Stockholm, Sweden.
Simplicio
Nicolas
N
Ferri
Anna L M
AL
Mira
Helena
H
Guillemot
François
F
Arenas
Ernest
E
Ang
Siew-Lan
SL
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D018398:Homeodomain Proteins / Q000378:metabolism; D017403:In Situ Hybridization; D060850:LIM-Homeodomain Proteins; D008297:Male; D008636:Mesencephalon / Q000166:cytology* / Q000196:embryology*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D055748:SOXB1 Transcription Factors; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D004298:Dopamine; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D055748:SOXB1 Transcription Factors; D015534:Trans-Activators; D014157:Transcription Factors; D014446:Tyrosine 3-Monooxygenase; C499317:Ascl1 protein, mouse; C112149:LIM homeobox transcription factor 1 beta; C102938:Neurog2 protein, mouse; C539883:Nr4a2 protein, mouse; C527783:Sox2 protein, mouse; C486336:Neurog1 protein, mouse