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Gata3 loss leads to embryonic lethality due to noradrenaline deficiency of the sympathetic nervous system

Abstract

Mouse embryos deficient in Gata3 die by 11 days post coitum (d.p.c.) from pathology of undetermined origin1. We recently showed that Gata3-directed lacZ expression of a 625-kb Gata3 YAC transgene in mice mimics endogenous Gata3 expression, except in thymus and the sympathoadrenal system2. As this transgene failed to overcome embryonic lethality (unpublished data and ref. 3) in Gata3−/− mice, we hypothesized that a neuroendocrine deficiency in the sympathetic nervous system (SNS) might cause embryonic lethality in these mutants. We find here that null mutation of Gata3 leads to reduced accumulation of Th (encoding tyrosine hydroxylase, Th) and Dbh (dopamine β-hydroxylase, Dbh) mRNA, whereas several other SNS genes are unaffected. We show that Th and Dbh deficiencies lead to reduced noradrenaline in the SNS, and that noradrenaline deficiency is a proximal cause of death in mutants by feeding catechol intermediates to pregnant dams, thereby partially averting Gata3 mutation-induced lethality. These older, pharmacologically rescued mutants revealed abnormalities that previously could not be detected in untreated mutants. These late embryonic defects include renal hypoplasia and developmental defects in structures derived from cephalic neural crest cells. Thus we have shown that Gata3 has a role in the differentiation of multiple cell lineages during embryogenesis.

Figure 1: Lack of Th expression in SG of Gata3-mutant embryos.
Figure 2: Th and Dbh mRNA and noradrenaline levels in Gata3-mutant embryos.
Figure 3: Catecholamine administration rescues Gata3-mutant embryos beyond their nominal time of death at 11 d.p.c.
Figure 4: Th is expressed in the CNS, but not in the para-aortic bodies or the adrenal glands, of Gata3-mutant embryos.
Figure 5: Developmental abnormalities in pharmacologically rescued Gata3 mutant embryos.

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Acknowledgements

We thank R. Palmiter, M. Yamamoto, K. Onodera, K. Tanimoto and Y. Zhou for discussions and help with the manuscript. Research support was provided by an NIH grant (GM28896; J.D.E.) and facility support by an NCI award to the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (CA60553).

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Correspondence to James Douglas Engel.

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Lim, KC., Lakshmanan, G., Crawford, S. et al. Gata3 loss leads to embryonic lethality due to noradrenaline deficiency of the sympathetic nervous system. Nat Genet 25, 209–212 (2000). https://doi.org/10.1038/76080

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