Abstract
Gata3 mutant mice expire of noradrenergic deficiency by embryonic day (E) 11 and can be rescued pharmacologically or, as shown here, by restoring Gata3 function specifically in sympathoadrenal (SA) lineages using the human DBH promoter to direct Gata3 transgenic expression. In Gata3-null embryos, there was significant impairment of SA differentiation and increased apoptosis in adrenal chromaffin cells and sympathetic neurons. Additionally, mRNA analyses of purified chromaffin cells from Gata3 mutants show that levels of Mash1, Hand2 and Phox2b (postulated upstream regulators of Gata3) as well as terminally differentiated SA lineage products (tyrosine hydroxylase, Th, and dopamine beta-hydroxylase, Dbh) are markedly altered. However, SA lineage-specific restoration of Gata3 function in the Gata3 mutant background rescues the expression phenotypes of the downstream, as well as the putative upstream genes. These data not only underscore the hypothesis that Gata3 is essential for the differentiation and survival of SA cells, but also suggest that their differentiation is controlled by mutually reinforcing feedback transcriptional interactions between Gata3, Mash1, Hand2 and Phox2b in the SA lineage.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adrenal Medulla / embryology*
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Adrenal Medulla / metabolism
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Adrenal Medulla / ultrastructure
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Amino Acid Transport System y+ / genetics
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Amino Acid Transport System y+ / metabolism
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Cell Differentiation*
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Cell Lineage
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Chromaffin Cells / chemistry
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Chromaffin Cells / cytology
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Chromaffin Cells / physiology
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Embryo, Mammalian / cytology
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Embryonic Development
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GATA3 Transcription Factor / analysis
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GATA3 Transcription Factor / genetics
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GATA3 Transcription Factor / metabolism*
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Ganglia, Sympathetic / embryology*
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Ganglia, Sympathetic / metabolism
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Ganglia, Sympathetic / ultrastructure
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Mice
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Mice, Transgenic
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Mixed Function Oxygenases / analysis
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Mixed Function Oxygenases / metabolism
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Mutation
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Neurons / chemistry
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Neurons / cytology
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Neurons / physiology*
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RNA, Messenger / analysis
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RNA, Messenger / metabolism
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Stem Cells / cytology
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription, Genetic
Substances
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Amino Acid Transport System y+
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Basic Helix-Loop-Helix Transcription Factors
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GATA3 Transcription Factor
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Gata3 protein, mouse
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Hand2 protein, mouse
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Homeodomain Proteins
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NBPhox protein
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RNA, Messenger
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Slc7a10 protein, mouse
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Transcription Factors
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Mixed Function Oxygenases