Dopamine Phenotype Research Articles

Does lineage determine the dopamine phenotype in the tadpole hypothalamus?: A quantitative analysis

The ancestry of dopaminergic (DA) neurons in the Xenopus laevis hypothalamus was investigated by combining intracellular lineage dye injections of 16- and 32-cell blastomeres with the immunofluorescent detection of tyrosine hydroxylase at tadpole stages. At these stages, DA neurons in the hypothalamus comprise a discrete nucleus that contains from 22 to 45 cells on each side [mean = 32.6 +/- 6.6 (SD)]. The DA nucleus descends from only four of the 16-cell blastomeres. The two dorsal midline blastomeres (D1.1) are the major progenitors, and in all embryos studied they contributed to the DA nucleus. The two dorsal lateral blastomeres (D1.2) contribute to the DA nucleus in only about half of the embryos. Thus, the DA nucleus descends only from a discrete group of progenitors, and the participation of some of the progenitors in the DA lineage is only probabilistic. The number of DA neurons generated by the same blastomere varied greatly in different animals. This variation in cell number correlated with the degree of coherence and the density of the clone in the hypothalamus, rather than with clonal ancestry. Bilateral deletion of the major 32-cell progenitor (D1.1.1) resulted in a nearly complete restitution of the DA nucleus in 74% of the embryos that successfully completed gastrulation and neurulation. In the rest, the hypothalamus was smaller than normal or missing, and the DA nucleus was significantly reduced in size or absent. These results show that the DA nucleus can be restored after its normal lineage is deleted, but complete regulation is not always accomplished. Several blastomere progenitors dramatically altered their contribution to the DA nucleus after D1.1.1 ablation, including two blastomeres that normally do not contribute to the DA lineage. Thus, the fate to produce DA neurons is not determined at cleavage stages.

Region‐specific consequences of PCD gene expression in the olfactory system

These studies investigated the response of olfactory bulb juxtaglomerular dopamine neurons to the loss of mitral cells in 6-7-month-old Purkinje cell degeneration (PCD) mice. Previous studies in normal mice, with tyrosine hydroxylase (TH) enzyme as a marker, demonstrated that following peripheral olfactory afferent denervation the juxtaglomerular dopamine neurons exhibited a large reduction in TH activity and immunoreactivity. These intrinsic dopamine neurons also receive afferent input via dendrodendritic contacts with mitral cells. In contrast to the deficits produced by peripheral denervation, following mitral cell degeneration in homozygous recessive PCD mice, TH activity and immunoreactivity were unaltered as compared to normal heterozygous littermates. Moreover, TH activity in the substantia nigra also was unchanged, thus suggesting that the dopamine phenotype is resistant to the influences of the pcd gene. Despite the absence of a well-defined effect of the pcd gene on neurons bearing the TH phenotype, the expression of this mutation within the olfactory system is not limited to mitral cell degeneration. The current studies also demonstrate the absence of the anterior commissure, especially pars anterior, in homozygous recessive PCD mice at 6-7 months postnatal. Whether or not the loss of the anterior commissure is a primary effect or one that is secondary to mitral cell degeneration, this structural alteration provides evidence that the pcd gene exerts more widespread effects within the olfactory system that previously appreciated. The neuronal specificity of those effects remains apparent as indicated by the lack of change in TH expression.

Unilateral, neonatal olfactory deprivation alters tyrosine hydroxylase expression but not aromatic amino acid decarboxylase or gaba immunoreactivity

Recent publications have demonstrated an important role for olfactory afferent innervation in maintenance of the dopamine phenotype of olfactory bulb target neurons. The mechanisms underlying the control of phenotypic expression in this system are not known. These studies employed the model of unilateral neonatal olfactory deprivation to investigate the effects of lack of odorant stimulation on dopamine expression in the rat. Immunoreactivity of tyrosine hydroxylase, the first and rate-limiting enzyme in dopamine biosynthesis, used as a marker of the dopamine system, exhibited a large decrease both 40 and 70 days following olfactory deprivation. The losses were region specific suggesting that the deprivation was not complete. The number of immunoreactive GABAergic neurons was not reduced. The number of neurons containing aromatic l-amino acid decarboxylase (the second enzyme in the dopamine biosynthetic pathway) was also not decreased. Olfactory marker protein immunoreactivity in the glomeruli, a marker for afferent innervation, was not significantly altered indicating that the olfactory bulb was not denervated. These data demonstrate that neonatal deprivation, and the resulting lack of odorant stimulation, produces a transneuronal alteration in dopamine expression without neuronal loss. The studies also suggest that neuronal activity or the activity-dependent release of a trophic factor is necessary for the expression of the dopamine phenotype.

Effect of Poliomyelitis on Sodium and Potassium in Serum and Urine

<h3>Abstract</h3> Midbrain dopamine (DA) neurons are associated with locomotor and psychiatric disorders. DA subtype is specified in ancestral neural precursor cells (NPCs) and maintained throughout neuronal differentiation. Here we show that endogenous expression of MeCP2 coincides with DA subtype specification in mouse mesencephalon, and premature expression of MeCP2 prevents in vitro cultured NPCs from acquiring DA subtype through interfering NURR1 transactivation of DA phenotype genes. By contrast, MeCP2 overexpression does not disturb DA subtype in DA neurons. By analyzing the dynamic change of DNA methylation along DA neuronal differentiation at the promoter of DA phenotype gene tyrosine hydroxylase (<i>Th</i>), we show that <i>Th</i> expression is determined by TET1-mediated de-methylation of NURR1 binding sites within <i>Th</i> promoter. Chromatin immunoprecipitation assays demonstrate that MeCP2 dominates the DNA binding of the corresponding sites thereby blocking TET1 function in DA NPCs, whereas TET1-mediated de-methylation prevents excessive MeCP2 binding in DA neurons. The significance of temporal DNA methylation status is further confirmed by targeted methylation/demethylation experiments showing that targeted de-methylation in DA NPCs protects DA subtype specification from MeCP2 overexpression, whereas targeted methylation disturbs subtype maintenance in MeCP2-overexpressed DA neurons. These findings suggest the appropriate timing of MeCP2 expression as a novel determining factor for guiding NPCs into DA lineage.