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

被引:265
作者
Lim, KC
Lakshmanan, G
Crawford, SE
Gu, Y
Grosveld, F
Engel, JD
机构
[1] Northwestern Univ, Dept Biochem Mol Biol & Cell Biol, Evanston, IL 60208 USA
[2] Northwestern Univ, Sch Med, Childrens Mem Inst Educ & Res, Dept Pathol, Evanston, IL 60208 USA
[3] Erasmus Univ, Dept Cell Biol & Genet, Rotterdam, Netherlands
关键词
D O I
10.1038/76080
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Mouse embryos deficient in Gata3 die by 11 days post coitum (d.p.c) from pathology of undetermined origin(1). 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(2). As this transgene failed to overcome embryonic lethality (unpublished data and ref. 3) in Gata3(-/-) mice, we hypothesized that a neuroendocrine deficiency in the sympathetic nervous system (SNS) might cause embryonic lethality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.
引用
收藏
页码:209 / 212
页数:4
相关论文
共 27 条
  • [1] The ErbB2 and ErbB3 receptors and their ligand, neuregulin-1, are essential for development of the sympathetic nervous system
    Britsch, S
    Li, L
    Kirchhoff, S
    Theuring, F
    Brinkmann, V
    Birchmeier, C
    Riethmacher, D
    [J]. GENES & DEVELOPMENT, 1998, 12 (12) : 1825 - 1836
  • [2] PAX-2 IS A DNA-BINDING PROTEIN EXPRESSED IN EMBRYONIC KIDNEY AND WILMS-TUMOR
    DRESSLER, GR
    DOUGLASS, EC
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (04) : 1179 - 1183
  • [3] Adrenergic nervous system in heart failure
    Esler, M
    Kaye, D
    Lambert, G
    Esler, D
    Jennings, G
    [J]. AMERICAN JOURNAL OF CARDIOLOGY, 1997, 80 (11A) : L7 - L14
  • [4] GEORGE KM, 1994, DEVELOPMENT, V120, P2673
  • [5] GROVES AK, 1995, DEVELOPMENT, V121, P887
  • [6] Hirsch MR, 1998, DEVELOPMENT, V125, P599
  • [7] HOYLE GW, 1994, J NEUROSCI, V14, P2455
  • [8] Joh T H, 1998, Adv Pharmacol, V42, P33
  • [9] Neuropilin-semaphorin III/D-mediated chemorepulsive signals play a crucial role in peripheral nerve projection in mice
    Kitsukawa, T
    Shimizu, M
    Sanbo, M
    Hirata, T
    Taniguchi, M
    Bekku, Y
    Yagi, T
    Fujisawa, H
    [J]. NEURON, 1997, 19 (05) : 995 - 1005
  • [10] TARGETED DISRUPTION OF THE TYROSINE-HYDROXYLASE LOCUS RESULTS IN SEVERE CATECHOLAMINE DEPLETION AND PERINATAL LETHALITY IN MICE
    KOBAYASHI, K
    MORITA, S
    SAWADA, H
    MIZUGUCHI, T
    YAMADA, K
    NAGATSU, I
    HATA, T
    WATANABE, Y
    FUJITA, K
    NAGATSU, T
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (45) : 27235 - 27243