Impaired mesenchymal cell function in Gata4 mutant mice leads to diaphragmatic hernias and primary lung defects
Impaired mesenchymal cell function in Gata4 mutant mice leads to diaphragmatic hernias and primary lung defects
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DOI：
10.1016/j.ydbio.2006.09.050
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发表时间：
2007-01-15
影响因子：
2.7
通讯作者：
Wilson, David B.
中科院分区：
文献类型：
--
作者：
Jay, Patrick Y.;Bielinska, Malgorzata;Wilson, David B.
先天性腹股沟疝（CDH）是一种经常致命的出生缺陷，通常与肺发育不全和心脏畸形有关。一些研究人员假设，这种缺陷的星座结果从遗传或环境触发器，破坏间充质细胞的功能，不仅在原始隔膜，但也胸部器官。另一种假设是，胸腔内腹腔脏器的移位继发性地干扰了心脏和肺的发育。最近，在人类和小鼠中，编码FOG-2（一种转录辅助调节因子）的基因的功能缺失突变与CDH和肺发育不全有关。在这里，我们表明，突变的基因加塔-4，一个转录因子已知的功能与FOG-2相互作用，使近交系小鼠的一组类似的出生缺陷。对野生型小鼠胚胎的分析表明，Gata 4和Fog 2在发育中的隔膜、肺和心脏的间充质细胞中共表达。Gata 4缺失突变杂合子的C57 B1/6小鼠的显著部分在出生后1天内死亡。杂合子的发育缺陷包括中线疝、远端气道扩张和心脏畸形。杂合子有这些缺陷的任何组合或没有。在嵌合体小鼠中，Gata 4（-/-）细胞保留了对血管中央腱和肺间充质中的细胞有贡献的能力，表明加塔-4对于这些谱系的分化不是必需的。我们的结论是，加塔-4，像它的辅助调节FOG-2，是需要适当的间充质细胞功能在发展中的隔膜，肺，心脏。(c)2006年爱思唯尔公司All rights reserved.
Congenital diaphragmatic hernia (CDH) is an often fatal birth defect that is commonly associated with pulmonary hypoplasia and cardiac malformations. Some investigators hypothesize that this constellation of defects results from genetic or environmental triggers that disrupt mesenchymal cell function in not only the primordial diaphragm but also the thoracic organs. The alternative hypothesis is that the displacement of the abdominal viscera in the chest secondarily perturbs the development of the heart and lungs. Recently, loss-of-function mutations in the gene encoding FOG-2, a transcriptional co-regulator, have been linked to CDH and pulmonary hypoplasia, in humans and mice. Here we show that mutagenesis of the gene for GATA-4, a transcription factor known to functionally interact with FOG-2, predisposes inbred mice to a similar set of birth defects. Analysis of wild-type mouse embryos demonstrated co-expression of Gata4 and Fog2 in mesenchymal cells of the developing diaphragm, lungs, and heart. A significant fraction of C57B1/6 mice heterozygous for a Gata4 deletion mutation died within 1 day of birth. Developmental defects in the heterozygotes included midline diaphragmatic hernias, dilated distal airways, and cardiac malformations. Heterozygotes had any combination of these defects or none. In chimeric mice, Gata4(-/-) cells retained the capacity to contribute to cells in the diaphragmatic central tendon and lung mesenchyme, indicating that GATA-4 is not required for differentiation of these lineages. We conclude that GATA-4, like its co-regulator FOG-2, is required for proper mesenchymal cell function in the developing diaphragm, lungs, and heart. (c) 2006 Elsevier Inc. All rights reserved.