Transcription factors FOXA1 and FOXA2 maintain dopaminergic neuronal properties and control feeding behavior in adult mice.
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.
The Francis Crick Institute Mill Hill Laboratory, London NW7 1AA, United Kingdom;
Alessandro
A
Pristerà
The Francis Crick Institute Mill Hill Laboratory, London NW7 1AA, United Kingdom;
Wei
W
Lin
Medical Research Council Brain Network Dynamics Unit, Department of Pharmacology, University of Oxford, Oxford OX1 3TH, United Kingdom;
Anna-Kristin
AK
Kaufmann
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom;
Katherine R
KR
Brimblecombe
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom; Oxford Parkinson's Disease Centre, University of Oxford, Oxford OX1 3PT, United Kingdom;
Sarah
S
Threlfell
Medical Research Council Brain Network Dynamics Unit, Department of Pharmacology, University of Oxford, Oxford OX1 3TH, United Kingdom; Oxford Parkinson's Disease Centre, University of Oxford, Oxford OX1 3PT, United Kingdom;
Paul D
http://orcid.org/0000-0003-0858-6088
PD
Dodson
Medical Research Council Brain Network Dynamics Unit, Department of Pharmacology, University of Oxford, Oxford OX1 3TH, United Kingdom; Oxford Parkinson's Disease Centre, University of Oxford, Oxford OX1 3PT, United Kingdom;
Peter J
PJ
Magill
Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, United Kingdom.
Cathy
C
Fernandes
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom; Oxford Parkinson's Disease Centre, University of Oxford, Oxford OX1 3PT, United Kingdom;
Stephanie J
SJ
Cragg
The Francis Crick Institute Mill Hill Laboratory, London NW7 1AA, United Kingdom; siew-lan.ang@crick.ac.uk.
Siew-Lan
SL
Ang
D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D005247:Feeding Behavior; D017353:Gene Deletion; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000502:physiology*; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics
C496500:Foxa1 protein, mouse; C496503:Foxa2 protein, mouse; D051541:Hepatocyte Nuclear Factor 3-alpha; D012333:RNA, Messenger; D051542:Hepatocyte Nuclear Factor 3-beta; D004298:Dopamine
FOXA1; FOXA2; burst firing; dopamine; feeding