Transcription factors FOXA1 and FOXA2 maintain dopaminergic neuronal properties and control feeding behavior in adult mice

Alessandro Pristerà, Wei Lin, Anna Kristin Kaufmann, Katherine R. Brimblecombe, Sarah Threlfell, Peter J. Magill, Paul Dodson, Cathy Fernandes, Stephanie J. Cragg, Siew Lan Ang

Research output: Contribution to journalArticle (Academic Journal)peer-review

26 Citations (Scopus)

Abstract

Midbrain dopaminergic (mDA) neurons are implicated in cognitive functions, neuropsychiatric disorders, and pathological conditions; hence understanding genes regulating their homeostasis has medical relevance. Transcription factors FOXA1 and FOXA2 (FOXA1/2) are key determinants of mDA neuronal identity during development, but their roles in adult mDA neurons are unknown. We used a conditional knockout strategy to specifically ablate FOXA1/2 in mDA neurons of adult mice. We show that deletion of Foxa1/2 results in down-regulation of tyrosine hydroxylase, the rate-limiting enzyme of dopamine (DA) biosynthesis, specifically in dopaminergic neurons of the substantia nigra pars compacta (SNc). In addition, DA synthesis and striatal DA transmission were reduced after Foxa1/2 deletion. Furthermore, the burst-firing activity characteristic of SNc mDA neurons was drastically reduced in the absence of FOXA1/2. These molecular and functional alterations lead to a severe feeding deficit in adult Foxa1/2 mutant mice, independently of motor control, which could be rescued by L-DOPA treatment. FOXA1/2 therefore control the maintenance of molecular and physiological properties of SNc mDA neurons and impact on feeding behavior in adult mice.

Original languageEnglish
Pages (from-to)E4929-E4938
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number35
DOIs
Publication statusPublished - 1 Sep 2015

Keywords

  • Burst firing
  • Dopamine
  • feeding
  • FOXA1
  • FOXA2

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