Premium
Hypoxia inducible factor (HIF)‐2α is required for the development of the catecholaminergic phenotype of sympathoadrenal cells
Author(s) -
Brown Stephen T.,
Kelly Kevin F.,
Daniel Juliet M.,
Nurse Colin A.
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06153.x
Subject(s) - tyrosine hydroxylase , catecholaminergic , endocrinology , medicine , biology , catecholamine , hypoxia inducible factors , chromaffin cell , dopamine , transcription factor , sympathoadrenal system , hypoxia (environmental) , adrenal medulla , catecholaminergic cell groups , tyrosine 3 monooxygenase , microbiology and biotechnology , chemistry , gene , biochemistry , organic chemistry , oxygen
The basic helix‐loop‐helix transcription factor, hypoxia inducible factor (HIF)‐2α has been implicated in the development of the catecholaminergic phenotype in cells of the sympathoadrenal (SA) lineage; however, the underlying mechanisms and HIF‐2α targets remain unclear. Using an immortalized rat adrenomedullary chromaffin cell line (MAH cells) derived from a fetal SA progenitor, we examined the role of HIF‐2α in catecholamine biosynthesis. Chronic hypoxia (2% O 2 , 24 h) induced HIF‐2α in MAH cells but expression of the rate‐limiting enzyme, tyrosine hydroxylase (TH) and catecholamine levels were unaltered. Interestingly, HIF‐2α depleted MAH cells showed dramatically lower (5–12 times) levels of dopamine and noradrenaline compared with wild‐type and scrambled controls, even in normoxia (21% O 2 ). This was correlated with a marked reduction in the expression of DOPA decarboxylase (DDC) and dopamine β hydroxylase (DβH) but not TH. Chromatin immunoprecipitation assays revealed that HIF‐2α was bound to the DDC gene promoter which contains two putative hypoxia response elements. These data suggest that a basal level of HIF‐2α function is required for the normal developmental expression of DDC and DβH in SA progenitor cells, and that loss of this function leads to impaired catecholamine biosynthesis.