Transcription factor AP-2β regulates the neurotransmitter phenotype and maturation of chromaffin cells.
During development, sympathetic neurons and chromaffin cells originate from bipotential sympathoadrenal (SA) progenitors arising from neural crests (NC) in the trunk regions. Recently, we showed that AP-2β, a member of the AP2 family, plays a critical role in the development of sympathetic neurons and locus coeruleus and their norepinephrine (NE) neurotransmitter phenotype. In the present study, we investigated the potential role of AP-2β in the development of NC-derived neuroendocrine chromaffin cells of the adrenal medulla and the epinephrine (EPI) phenotype determination. In support of its role in chromaffin cell development, AP-2β is prominently expressed in both embryonic and adult adrenal medulla. In adrenal chromaffin cells of the AP-2β(-/-) mouse, the expression levels of catecholamine biosynthesizing enzymes, dopamine β-hydroxylase (DBH) and phenylethanolamine-N-methyl-transferase (PNMT), as well as the SA-specific transcription factor, Phox2b, are significantly reduced compared to wild type. In addition, ultrastructural analysis demonstrated that the formation of large secretory vesicles, a hallmark of differentiated chromaffin cells, is defective in AP-2β(-/-) mice. Furthermore, the level of EPI content is largely diminished (>80%) in the adrenal gland of AP-2β(-/-) mice. Chromatin immunoprecipitation (ChIP) assays of rat adrenal gland showed that AP-2β binds to the upstream promoter of the PNMT gene in vivo; strongly suggesting that it is a direct target gene. Overall, our data suggest that AP-2β plays critical roles in the epinephrine phenotype and maturation of adrenal chromaffin cells.
Hong
Seok Jong
SJ
Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA. seok-hong@northwestern.edu
Huh
Yang Hoon
YH
Leung
Amanda
A
Choi
Hyun Jin
HJ
Ding
Yunmin
Y
Kang
Un Jung
UJ
Yoo
Seung Hyun
SH
Buettner
Reinhard
R
Kim
Kwang-Soo
KS
D000311:Adrenal Glands / Q000166:cytology / Q000378:metabolism; D000320:Adrenergic Fibers / Q000378:metabolism; D000818:Animals; D019439:Chromaffin Cells / Q000166:cytology / Q000502:physiology*; D004837:Epinephrine / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D051379:Mice; D018345:Mice, Knockout; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D010641:Phenotype; D010625:Phenylethanolamine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D022142:Secretory Vesicles / Q000648:ultrastructure; D050656:Transcription Factor AP-2 / Q000235:genetics / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D018377:Neurotransmitter Agents; D050656:Transcription Factor AP-2; D014446:Tyrosine 3-Monooxygenase; D010625:Phenylethanolamine N-Methyltransferase; D009638:Norepinephrine; D004837:Epinephrine