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

PristerĂ  A., Lin W., Kaufmann A-K., Brimblecombe KR., Threlfell S., Dodson PD., Magill PJ., Fernandes C., Cragg SJ., Ang S-L.

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.

DOI

10.1073/pnas.1503911112

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

01/09/2015

Volume

112

Pages

E4929 - E4938

Keywords

FOXA1, FOXA2, burst firing, dopamine, feeding, Animals, Brain, Dopamine, Feeding Behavior, Gene Deletion, Hepatocyte Nuclear Factor 3-alpha, Hepatocyte Nuclear Factor 3-beta, Mice, Mice, Knockout, Neurons, RNA, Messenger

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