Abstract
The proteins Foxa1 and Foxa2 belong to the forkhead family of transcription factors and are involved in the development of several tissues, including liver, pancreas, lung, prostate, and the neural system. Both Foxa1 and Foxa2 are also crucial for the specification and differentiation of dopamine (DA) neurons during embryonic development, while about 30% of mice with an embryonic deletion of a single allele of the Foxa2 gene exhibit an age-related asymmetric loss of DA neurons and develop locomotor symptoms resembling Parkinson's disease (PD). Notably, both Foxa1 and Foxa2 factors continue to be expressed in the adult dopamine system. To directly assess their functions selectively in adult DA neurons, we induced genetic deletions of Foxa1/2 transcription factors in mice using a tamoxifen inducible tissue-specific CreERT2 recombinase expressed under control of the dopamine transporter (DAT) promoter (DATCreERT2). The conditional DA neurons-specific ablation of both genes, but not of Foxa2 alone, in early adulthood, caused a decline of striatal dopamine and its metabolites, along with locomotor deficits. At early pre-symptomatic stages, we observed a decline in aldehyde dehydrogenase family 1, subfamily A1 (Aldh1a1) protein expression in DA neurons. Further analyses revealed a decline of aromatic amino acid decarboxylase (AADC) and a complete loss of DAT expression in these neurons. These molecular changes ultimately led to a reduction of DA neuron numbers in the substantia nigra pars compacta (SNpc) of aged cFoxa1/2−/− mice, resembling the progressive course of PD in humans. Altogether, in this study, we address the molecular, cellular, and functional role of both Foxa1 and Foxa2 factors in the maintenance of the adult dopamine system which may help to find better approaches for PD treatment.
Highlights
Parkinson’s disease (PD) is one of the most prevalent age-related movement disorders occurring in about 1% of the population above the age of 60 (Abou-Sleiman et al, 2006; Ferri et al, 2007)
The previous works delineating the role of Foxa factors in the liver, pancreas and developing DA neurons (Ferri et al, 2007; Kaestner, 2010; Stott et al, 2013) have detected striking similarities in binding motifs, regulated genes and global functions of Foxa1 and Foxa2 factors, indicating that Foxa1 could compensate for the function of Foxa2 in adult DA neurons of cFoxa2−/− mice
Despite significant down-regulation of Foxa2 mRNA levels in the ventral midbrain of cFoxa2−/− mice, the levels of Foxa1 in these animals were up-regulated (Figure 1D). These results imply the existence of a functional overlap between Foxa1 and Foxa2 in adult DA neurons
Summary
Parkinson’s disease (PD) is one of the most prevalent age-related movement disorders occurring in about 1% of the population above the age of 60 (Abou-Sleiman et al, 2006; Ferri et al, 2007). The development of midbrain DA neurons is a highly orchestrated process involving coordinated action of multiple signaling molecules and transcription factors, such as Shh, Wnt, Otx, Pitx, Nurr (Nr4a2), Foxa, and Foxa (Perlmann and WallenMackenzie, 2004; Ferri et al, 2007; Smidt and Burbach, 2007; Omodei et al, 2008; Jacobs et al, 2009; Joksimovic et al, 2009; Mesman et al, 2014) Several of these factors continue to be expressed in post-mitotic and in adult DA neurons contributing to the functional maintenance of this neuronal population. A selective ablation of orphan nuclear receptor Nurr in adult DA neurons using a tamoxifen (TAM)-inducible Cre/LoxP recombination system leads to the fiber pathology of this neuronal population and loss of Frontiers in Cellular Neuroscience www.frontiersin.org
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