title: Foxa1 is essential for development and functional integrity of the subthalamic nucleus.
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.
authors.affiliation: Institute of Molecular Health Sciences, ETH Zurich, 8903 Zurich, Switzerland.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Gasser
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Helge C
authors.initials: HC
authors.lastname: Johannssen
authors.affiliation: Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rülicke
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland.|Institute of Pharmaceutical Sciences, ETH Zurich, 8903 Zurich, Switzerland.
authors.forename: Hanns Ulrich
authors.initials: HU
authors.lastname: Zeilhofer
authors.affiliation: Institute of Molecular Health Sciences, ETH Zurich, 8903 Zurich, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Stoffel
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D020043:Genes, Essential; D017930:Genes, Reporter; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics* / Q000378:metabolism; D006948:Hyperkinesis / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D038081:Organogenesis / Q000235:genetics; D020531:Subthalamic Nucleus / Q000196:embryology / Q000502:physiology*; D059467:Transcriptome
chemical_list: C496500:Foxa1 protein, mouse; D051541:Hepatocyte Nuclear Factor 3-alpha