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A second independent pathway for development of mesencephalic dopaminergic neurons requires Lmx1b

Abstract

We identified the LIM homeodomain transcription factor Lmx1b in the mesencephalic dopamine (mesDA) systems of embryos and adults. Analysis of spatiotemporal expression in Lmx1b null mutants and wild-type mice implicated a cascade involving Lmx1b in the early development of mesDA neurons. Although disruption of this cascade did not block induction of tyrosine hydroxylase (TH), a key enzyme in DA synthesis, or Nurr1, a nuclear hormone receptor, Lmx1b knockout mice failed to induce the mesDA-specific homeodomain gene Ptx3 in TH-positive neurons. Eventually, this small set of TH-positive neurons was lost during embryonic maturation. The data suggest that at least two molecular cascades operate during the specification of the mesDA system, one specifying neurotransmitter phenotype and another essential for other aspects of mesDA neuron differentiation.

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Figure 1: Expression of Lmx1b in the rat nervous system.
Figure 2: Colocalization of Ptx3 protein and Lmx1b transcripts in mesencephalic dopaminergic neurons.
Figure 3: Lmx1bexpression in the human substantia nigra (SN).
Figure 4: Expression of mesDA markers TH and Ptx3 in E12.5 Lmx1b null mutants (Lmx1b−/− E12.5) compared with E12.5 wild-type animals (WT E12.5).
Figure 5: Expression of Nurr1 in Lmx1b knockout (Lmx1b−/−) E12.5 animals compared with Nurr1 expression in age-matched wild-type controls.
Figure 6: Expression of Lmx1b in sagittal sections of Nurr1 knockout (−/−) animals compared with expression in wild-type controls.
Figure 7: TH expression in wild-type (a, b) and Lmx1b−/− (ce) mouse brains at stages E12.5 and E18.5.

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Acknowledgements

We acknowledge P. Voorn and the Netherlands Brain Bank for providing sections of human brain tissue, G. Wolterink for providing the 6-OHDA-lesioned animals and O.M. Conneely for providing the Nurr1 null-mutant embryos. This work was supported by grants from the Netherlands Organization for Scientific Research (ALW: 805-33.211-p), the Korczak Foundation for Autism and Related Disorders and the National Parkinson Foundation, USA. We also acknowledge the Wijnand M. Pon foundation for financial support.

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Correspondence to J. Peter H. Burbach.

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Smidt, M., Asbreuk, C., Cox, J. et al. A second independent pathway for development of mesencephalic dopaminergic neurons requires Lmx1b. Nat Neurosci 3, 337–341 (2000). https://doi.org/10.1038/73902

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