Regulation of the noradrenaline neurotransmitter phenotype by the transcription factor AP-2beta.
AP-2 family transcription factors are essential for development and morphogenesis of diverse tissues and organs, but their precise roles in specification of neural crest stem cell (NCSC)-derived cell types have not been determined. Among three members known to be expressed in the NCSC (i.e. AP-2alpha, AP-2beta, and AP-2gamma), we found that only AP-2beta is predominantly expressed in the sympathetic ganglia of developing mouse embryos, supporting its role in sympathetic development. Indeed, AP-2beta null mice expressed significantly reduced levels of both noradrenaline (NA) and NA-synthesizing dopamine beta-hydroxylase in the peripheral nervous system. Strikingly, we also found that NA neuron development was significantly compromised in the locus coeruleus as well. Pharmacological treatment with an NA intermediate during pregnancy significantly rescues the neonatal lethality of AP-2beta(-/-) mice, indicating that NA deficiency is one of the main causes for lethality found in AP-2beta(-/-) mice. We also showed that forced expression of AP-2beta, but not other AP-2 factors, in NCSC favors their differentiation into NA neurons. In summary, we propose that AP-2beta plays critical and distinctive roles in the NA phenotype specification in both the peripheral and central nervous system during development.
Hong
Seok Jong
SJ
Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02478, USA.
Lardaro
Thomas
T
Oh
Myung Sook
MS
Huh
Youngbuhm
Y
Ding
Yunmin
Y
Kang
Un Jung
UJ
Kirfel
Jutta
J
Buettner
Reinhard
R
Kim
Kwang-Soo
KS
D000818:Animals; D002490:Central Nervous System / Q000196:embryology* / Q000378:metabolism; D002642:Chick Embryo; D004299:Dopamine beta-Hydroxylase / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D017933:Peripheral Nervous System / Q000196:embryology* / Q000378:metabolism; D010641:Phenotype; D014018:Tissue Distribution; D050656:Transcription Factor AP-2 / Q000378:metabolism / Q000502:physiology*
D050656:Transcription Factor AP-2; D004299:Dopamine beta-Hydroxylase; D009638:Norepinephrine