Foxa1 and Foxa2 function both upstream of and cooperatively with Lmx1a and Lmx1b in a feedforward loop promoting mesodiencephalic dopaminergic neuron development.
Mesodiencephalic dopaminergic neurons control voluntary movement and reward based behaviours. Their dysfunction can lead to neurological disorders, including Parkinson's disease. These neurons are thought to arise from progenitors in the floor plate of the caudal diencephalon and midbrain. Members of the Foxa family of forkhead/winged helix transcription factor, Foxa1 and Foxa2, have previously been shown to regulate neuronal specification and differentiation of mesodiencephalic progenitors. However, Foxa1 and Foxa2 are also expressed earlier during regional specification of the rostral brain. In this paper, we have examined the early function of Foxa1 and Foxa2 using conditional mutant mice. Our studies show that Foxa1 and Foxa2 positively regulate Lmx1a and Lmx1b expression and inhibit Nkx2.2 expression in mesodiencephalic dopaminergic progenitors. Subsequently, Foxa1 and Foxa2 function cooperatively with Lmx1a and Lmx1b to regulate differentiation of mesodiencephalic dopaminergic neurons. Chromatin immunoprecipitation experiments indicate that Nkx2.2 and TH genes are likely direct targets of Foxa1 and Foxa2 in mesodiencephalic dopaminergic cells in vivo. Foxa1 and Foxa2 also inhibit GABAergic neuron differentiation by repressing the Helt gene in the ventral midbrain. Our data therefore provide new insights into the specification and differentiation of mesodiencephalic dopaminergic neurons and identifies Foxa1 and Foxa2 as essential regulators in these processes.
Lin
Wei
W
Division of Developmental Neurobiology, MRC National Institute for Medical Research, The Ridgeway, London, NW7 1AA, UK.
Metzakopian
Emmanouil
E
Mavromatakis
Yannis E
YE
Gao
Nan
N
Balaskas
Nikolaos
N
Sasaki
Hiroshi
H
Briscoe
James
J
Whitsett
Jeffrey A
JA
Goulding
Martyn
M
Kaestner
Klaus H
KH
Ang
Siew-Lan
SL
D000818:Animals; D001921:Brain / Q000196:embryology* / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D047369:Chromatin Immunoprecipitation; D004298:Dopamine / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism / Q000502:physiology*; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism / Q000502:physiology*; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000378:metabolism*; D060850:LIM-Homeodomain Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology; D014157:Transcription Factors / Q000378:metabolism*; D029961:Zebrafish Proteins
C496500:Foxa1 protein, mouse; C496503:Foxa2 protein, mouse; D051541:Hepatocyte Nuclear Factor 3-alpha; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; C112149:LIM homeobox transcription factor 1 beta; D060850:LIM-Homeodomain Proteins; C489692:Lmx1a protein, mouse; C000715627:Nkx2-2 protein, mouse; D014157:Transcription Factors; D029961:Zebrafish Proteins; C000715630:nkx2.2b protein, zebrafish; D051542:Hepatocyte Nuclear Factor 3-beta; D004298:Dopamine