Early developmental failure of substantia nigra dopamine neurons in mice lacking the homeodomain genePitx3

Abstract

The mesencephalic dopamine (mesDA) system is involved in the control of movement and behavior. The expression of Pitx3 in the brain is restricted to the mesDA system and the gene is induced relatively late, at E11.5, a time when tyrosine hydroxylase (Th) gene expression is initiated. We show here that, in the Pitx3-deficient aphakia(ak) mouse mutant, the mesDA system is malformed. Owing to the developmental failure of mesDA neurons in the lateral field of the midbrain,mesDA neurons are not found in the SNc and the projections to the caudate putamen are selectively lost. However, Pitx3 is expressed in all mesDA neurons in control animals. Therefore, mesDA neurons react specifically to the loss of Pitx3. Defects of motor control where not seen in the ak mice,suggesting that other neuronal systems compensate for the absence of the nigrostriatal pathway. However, an overall lower activity was observed. The results suggest that Pitx3 is specifically required for the formation of the SNc subfield at the onset of dopaminergic neuron differentiation.

Motor deficits and altered striatal gene expression in aphakia (ak) mice

“…Additionally, it is unclear how the striatal transcriptome responds to persistent dopaminergic denervation over time. Studies have reported increased, decreased or unchanged mRNA expression levels of dopamine receptors and neuropeptides in ak mice (Smidt et al, 2004;Smits et al, 2005;van den Munckhof et al, 2006). These inconsistencies may lie in differing methodologies used to assess striatal expression of these proteins or their transcripts.…”

“…The Pitx3 −/− or aphakia (ak) mouse is a promising model of striatal denervation in PD as it exhibits the cell specificity of neurodegeneration observed in humans (Hwang et al, 2003;Nunes et al, 2003;Smidt et al, 2004), similar neuroadaptive phenomena at the level of the striatum (Smits et al, 2005;van den Munckhof et al, 2006), and locomotor deficits that are rescued by levodopa van den Munckhof et al, 2006). Pitx3 is a member of the pituitary family of bicoid type homeobox transcription factors (Semina et al, 1997).…”

“…In homozygous ak mice, genomic deletions within the promoter and exon1 of the Pitx3 gene (Rieger et al, 2001;Semina et al, 2000) result in incomplete lens development and aphakia. Undetectable expression of Pitx3 protein in the midbrain is accompanied by failed development of approximately 90% of SNc neurons, and severe reduction of dorsal striatal dopaminergic innervation (Hwang et al, 2003;Nunes et al, 2003;Smidt et al, 2004;van den Munckhof et al, 2003). The ak mouse retains expression of Pitx3 in skeletal muscle (L'Honoré et al, 2007).…”

“…In homozygote ak mice, SNc cell loss (particularly in the ventral nigra) is almost complete by birth, whereas the ventral tegmental area (VTA) undergoes progressive postnatal cell loss (Nunes et al, 2003;van den Munckhof et al, 2003) so that approximately 50% of this region is lost by 100 days (van den Munckhof et al, 2003). Ak mice exhibit relatively subtle behavioral and motor deficits (Hwang et al, 2003;van den Munckhof et al, 2003;, and some conflicting data exist in this regard (Smidt et al, 2004;Hwang et al, 2005). It is not known whether motor signs progress with age in ak mice.…”

Cooperative transcription activation by Nurr1 and Pitx3 induces embryonic stem cell maturation to the midbrain dopamine neuron phenotype

“…Expression analyses and loss-of-function knockout mouse studies have revealed roles for additional transcription factors in the specification and maturation of midbrain DA neurons, including the homeodomain proteins Lmx1b (5), Pitx3 (6)(7)(8)(9), and En1 (10,11). None of these factors are uniquely expressed in midbrain DA neurons, nor are they required for TH expression.…”