TRANSCRIPTION FACTOR NURR1 IS REQUIRED FOR DOPAMINE NEUROGENESIS. Lars
Olson1, Rolf Zetterstrom2, Ludmila Solomin2,
Lottie Jansson2, Barry Hoffer3, and Thomas Perlmann2.
1Department of Neuroscience, Karolinska Institute, Stockholm,
2The Ludwig Institute for Cancer Research, Stockholm Branch,
3Intramural Research Program, NIDA, NIH, Baltimore, MD.
to a subfamily of orphan nuclear receptor transcription factors which also
includes NGFI-B and Nor1. In situ hybridization demonstrates partly overlapping
and partly unique cellular expression patterns in the developing and adult
nervous system. These patterns will be reviewed. All three factors can
bind to DNA as monomers and cause constitutive transcription. Interestingly,
Nurr1 and NGFI-B, but not Nor1 can also heterodimerize with RXR. In such
heterodimers, RXR can be activated by a vitamin A ligand. The functional
and neuroanatomical studies therefore indicate possible redundancy between
members of this subfamily of the steroid/thyroid hormone receptor superfamily.
Midbrain dopamine (DA) neurons, however, express only Nurr1, making redundancy
impossible in this region. Moreover, Nurr1 mRNA is found in the developing
mesencephalic flexure area, prior to any known marker of DA neurons. When
mice were generated in which functional Nurr1 mRNA expression had been
eliminated, we found a complete absence of DA neurons. Detailed studies
of Nurr1 -/- mice, using a host of markers for the DA neuron phenotype
supports the conclusion that these neurons fail do be formed in the absence
of the transcription factor. Nurr1 -/- mice die within 24 hours after birth,
and appear unable to suckle and feed themselves. The exact mechanism behind
this early postnatal lethality remains to be explained. Although the CNS
and peripheral organs appear grossly normal in the knockouts, we currently
favor the hypothesis that the animals succumb so soon after birth for other
reasons than the lack of the nigrostriatal DA system.
[Abstract Titles] [Anderson] [Bolz] [Chugani] [Levitt] [Zhou]