Abstract
Mouse embryos deficient in Gata3 die by 11 days post coitum (d.p.c.) from pathology of undetermined origin. 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 system. As this transgene failed to overcome embryonic lethality (unpublished data and ref. 3) in Gata3-/- mice, we hypothesized that a neuroendocrine deficiency in the sympathetic nervous system (SNS) might cause embryonic lethality in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 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 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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Crosses, Genetic
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DNA-Binding Proteins / deficiency*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Dihydroxyphenylalanine / administration & dosage
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Dihydroxyphenylalanine / pharmacology
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Dopamine beta-Hydroxylase / deficiency
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Dopamine beta-Hydroxylase / genetics
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Droxidopa / administration & dosage
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Droxidopa / pharmacology
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Embryo, Mammalian / drug effects
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Embryo, Mammalian / embryology
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Embryo, Mammalian / metabolism
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Embryonic and Fetal Development / genetics*
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Female
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GATA3 Transcription Factor
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Gene Deletion
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Genes, Lethal / genetics
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Genotype
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Kidney / abnormalities
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Kidney / drug effects
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Kidney / embryology
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Kidney / metabolism
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Male
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Mice
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Mice, Knockout
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Neural Crest / abnormalities
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Neural Crest / drug effects
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Neural Crest / embryology
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Neural Crest / metabolism
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Norepinephrine / administration & dosage
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Norepinephrine / deficiency*
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Norepinephrine / metabolism
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Norepinephrine / pharmacology
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Phenotype
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Pregnancy
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Sympathetic Nervous System / abnormalities
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Sympathetic Nervous System / drug effects
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Sympathetic Nervous System / embryology*
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Sympathetic Nervous System / metabolism
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Trans-Activators / deficiency*
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Trans-Activators / genetics
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Trans-Activators / physiology*
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Tyrosine 3-Monooxygenase / deficiency
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Tyrosine 3-Monooxygenase / genetics
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Tyrosine 3-Monooxygenase / metabolism
Substances
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DNA-Binding Proteins
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GATA3 Transcription Factor
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Gata3 protein, mouse
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RNA, Messenger
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Trans-Activators
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Dihydroxyphenylalanine
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Tyrosine 3-Monooxygenase
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Dopamine beta-Hydroxylase
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Droxidopa
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Norepinephrine