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

Mouse embryos deficient in Gata3 die by 11 days post coitum (d.p.c) from pa thology of undetermined origin(1). We recently showed that Gata3-directed l acZ expression of a 625-kb Gata3 YAC transgene in mice mimics endogenous Ga ta3 expression, except in thymus and the sympathoadrenal system(2). As this transgene failed to overcome embryonic lethality (unpublished data and ref . 3) in Gata3(-/-) mice, we hypothesized that a neuroendocrine deficiency i n the sympathetic nervous system (SNS) might cause embryonic lethality in t hese mutants. We find here that null mutation of Gata3 leads to reduced acc umulation of Th (encoding tyrosine hydroxylase, Th) and Dbh (dopamine beta- 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 avert ing Gata3 mutation-induced lethality. These older, pharmacologically rescue d mutants revealed abnormalities that previously could not be detected in u ntreated mutants. These late embryonic defects include renal hypoplasia and developmental defects in structures derived from cephalic neural crest cel ls. Thus we have shown that Gata3 has a role in the differentiation of mult iple cell lineages during embryogenesis.