Selective deficits in the expression of striatal‐enriched mRNAs in Huntington's disease

Abstract

We have identified and cataloged 54 genes that exhibit predominant expression in the striatum. Our hypothesis is that such mRNA molecules are likely to encode proteins that are preferentially associated with particular physiological processes intrinsic to striatal neurons, and therefore might contribute to the regional specificity of neurodegeneration observed in striatal disorders such as Huntington's disease (HD). Expression of these genes was measured simultaneously in the striatum of HD R6/1 transgenic mice using Affymetrix oligonucleotide arrays. We found a decrease in expression of 81% of striatum-enriched genes in HD transgenic mice. Changes in expression of genes associated with G-protein signaling and calcium homeostasis were highlighted. The most striking decrement was observed for a newly identified subunit of the sodium channel, beta 4, with dramatic decreases in expression beginning at 8 weeks of age. A subset of striatal genes was tested by real-time PCR in caudate samples from human HD patients. Similar alterations in expression were observed in human HD and the R6/1 model for the striatal genes tested. Expression of 15 of the striatumenriched genes was measured in 6-hydroxydopaminelesioned rats to determine their dependence on dopamine innervation. No changes in expression were observed for any of these genes. These findings demonstrate that mutant huntingtin protein causes selective deficits in the expression of mRNAs responsible for striatum-specific physiology and these may contribute to the regional specificity of degeneration observed in HD.

Functional roles for the striatal-enriched transcription factor, Bcl11b, in the control of striatal gene expression and transcriptional dysregulation in Huntington's disease

“…In this study, we further investigated CNS-wide expression of Bcl11b protein and gene expression changes in R6/1 transgenic mice at different stages of disease, as well as in post-mortem caudate samples from human subjects with HD. In addition to showing high levels of expression in the striatum, Bcl11b mRNA is also expressed in other brain regions affected in HD, such as cortex, hippocampus and olfactory bulb from early embryonic stages of development (Leid et al, 2004;Arlotta et al 2005;Desplats et al 2006). Immunohistochemistry experiments on adult mouse brain (>2 months of age) demonstrate that Bcl11b protein expression is also expressed in these regions ( Figure 1).…”

“…Our initial studies showed decreased expression of Bcl11b mRNA in the striata of symptomatic R6/1 transgenic mice (Desplats et al 2006). In this study, we further investigated CNS-wide expression of Bcl11b protein and gene expression changes in R6/1 transgenic mice at different stages of disease, as well as in post-mortem caudate samples from human subjects with HD.…”

“…However, other mechanisms of transcription factor disruption due to mutant htt have been proposed (Chen-Plotkin et al, 2006;Sadri-Vakili et al, 2007). Overall, there is much evidence that mutant htt disrupts transcriptional regulation; consequential of this concept are gene profiling studies that have revealed dramatic expression alterations of genes, especially those exhibiting enriched expression in the striatum, in the brains of HD mouse models and human subjects with HD (Luthi-Carter et al, 2000;Zucker et al, 2005;Desplats et al, 2006;Hodges et al, 2006;Thomas 2006). While this model is widely accepted, it does not establish how only specific neuronal populations are affected in HD.…”

“…Real-time PCR experiments were performed using the ABI PRISMs 7900HT Sequence Detection System (Applied Biosystems, Foster City, CA) as described previously (Desplats et al 2006). Amplification was performed on a cDNA amount equivalent to 25 ng total RNA with 1 x SYBR ® Green universal PCR Master mix (Applied Biosystems) containing deoxyribonucleotide triphosphates, MgCl 2 , AmpliTaq Gold DNA polymerase, and forward and reverse primers.…”

“…CTIP2), that showed enriched expression in the striatum and was decreased in the brains of R6/1 transgenic mice (Desplats et al 2006). Bcl11b is a C 2 H 2 zinc finger DNA binding protein that has been shown to alter transcription in vitro by interacting with chicken ovalbumin upstream promoter transcription factor (COUP-TF) family members (Avram et al, 2000), or via a sequence-specific DNA binding element that is related to the canonical GC box (Avram et al, 2002).…”