Abstract
Inactivation of transcription factor Foxa1 in mice results in neonatal mortality of unknown cause. Here, we report that ablation of Foxa1 causes impaired development and loss of the subthalamic nucleus (STN). Functional deficits in the STN have been implicated in the etiology of Huntington’s and Parkinson’s disease. We show that neuronal ablation by Synapsin1-Cre-mediated Foxa1 deletion is sufficient to induce hyperlocomotion in mice. Transcriptome profiling of STN neurons in conditional Foxa1 knockout mice revealed changes in gene expression reminiscent of those in neurodegenerative diseases. We identified Ppargc1a, a transcriptional co-activator that is implicated in neurodegeneration, as a Foxa1 target. These findings were substantiated by the observation of Foxa1-dependent demise of STN neurons in conditional models of Foxa1 mutant mice. Finally, we show that the spontaneous firing activity of Foxa1-deficient STN neurons is profoundly impaired. Our data reveal so far elusive roles of Foxa1 in the development and maintenance of STN function.
Highlights
EGFP, the polyadenylation sequence (PA) and the Neomycin (NEO) selection cassette
Prominent Foxa1eGFP expression was detected in the perikarya of the subthalamic nucleus (STN), the ventral premammillary nucleus, the supramammillary nuclei, the posterior hypothalamic area and the ventral tegmental area (VTA) (Figs S2 and S3A,B)
We found a significant fraction of STN-enriched transcripts to be depleted from sorted Foxa1eGFP neurons of newborn Foxa1∆/∆ (∆Foxa1) mice, when compared to their Foxa1fl/fl littermates (Table S2)
Summary
EGFP, the polyadenylation sequence (PA) and the Neomycin (NEO) selection cassette. Expression from the recombined BAC transgene yields a fusion protein consisting of the N-terminal 31 amino acids of Foxa[1] fused to eGFP. (B) Immunohistochemical and RNA in situ hybridization analysis of STN-enriched proteins (Foxp[2], Calb2) or transcripts (Pitx[2], Nts, C130021I20Rik) on coronal brain sections of newborn ∆Foxa[1] mice (P0). Expression from the recombined BAC transgene yields a fusion protein consisting of the N-terminal 31 amino acids of Foxa[1] fused to eGFP. (C,D) Immunohistochemical analysis of (C) Foxa1eGFP or (D) Foxa1eGFP, Hoechst and NeuN on coronal brain sections of newborn ∆Foxa[1] mice (P0). In this study we analyzed the expression of Foxa[1] in the brain, using a BAC transgenic Foxa[1] reporter mouse model. We detected strong Foxa[1] expression in the developing and adult STN and studied the consequences of Foxa[1] ablation on STN development and function. We found that Foxa[1] is absolutely required for the formation of the STN and that the conditional deletion of Foxa[1] from post-mitotic neurons causes a hyperkinetic state in animals, accompanied by neurodegeneration and functional deficits in the STN
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