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First published online 30 August 2006
doi: 10.1242/dev.02553

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Gata3 participates in a complex transcriptional feedback network to regulate sympathoadrenal differentiation

¹ Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba 305-8575, Japan.
² Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109-0616, USA.
³ Department of Biochemistry, University of Calgary, Canada.
⁴ Department of Pathology and Laboratory Medicine, Children's Memorial Hospital, Feinberg School of Medicine, Northwestern University, Chicago, IL 60614-3394, USA.
⁵ Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba 305-8575, Japan.
⁶ Laboratory Animal Resource Center, University of Tsukuba, Tsukuba 305-8575, Japan.

^* Author for correspondence (e-mail: engel{at}umich.edu)

Accepted 27 July 2006

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 ß-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.

Key words: Gata3, Chromaffin cells, Sympathetic neurons, Tyrosine hydroxylase, Dopamine ß-hydroxylase

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