The molecular and cellular basis of variable craniofacial phenotypes and their genetic rescue in Twisted gastrulation mutant mice
The molecular and cellular basis of variable craniofacial phenotypes and their genetic rescue in Twisted gastrulation mutant mice
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DOI：
10.1016/j.ydbio.2011.04.026
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发表时间：
2011-07-01
影响因子：
2.7
通讯作者：
Petryk, Anna
中科院分区：
文献类型：
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作者：
Billington, Charles J., Jr.;Ng, Brandon;Petryk, Anna
尽管有共同的遗传原因，但许多发育异常的严重程度可能差异很大。扭曲原肠胚形成（Twsg 1（-/-））缺陷的小鼠表现出这种表型变异，在同基因C57 BL/6品系背景下出现广泛的颅面畸形。为了研究这种降低的表达率和可变表达率的分子基础，我们使用外显子微阵列分析了几种不同的，形态学定义的Twsg 1（-/-）和野生型（WT）胚胎的下颌弓中的基因表达。转录水平的层次聚类分析确定了许多差异表达的基因，明确区分严重影响和未受影响的Twsg 1（-/-）突变体从WT胚胎。几个在颅面发育中起着众所周知作用的基因在未受影响的Twsg 1（-/-）突变胚胎中上调，这表明它们可能弥补了TWSG 1的缺失。印记基因在差异表达的基因中比例过高，特别是在受影响和未受影响的突变体之间。受影响最严重的胚胎表现出p53信号的增加及其靶点Trp 53 inp 1的表达增加。随着p53基因剂量的降低，颅面缺陷的频率显著降低，从Twsg 1（-/-）/p53（+/+）幼仔（N = 675）的44%降至Twsg 1（-/-）p53（+/-）的30%（N = 47，p=0.04）和Twsg 1（-/-）同窝仔的15%（N = 39，p = 0.001）。总之，这些结果表明，Twsg 1（-/-）小鼠的表型变异与某些发育调控基因的差异表达有关，颅面缺陷可以通过降低p53水平部分挽救。我们推测，变量响应压力可能有助于变量颅面表型，通过触发差异表达的基因和变量细胞凋亡。(C)2011 Elsevier Inc. All rights reserved.
The severity of numerous developmental abnormalities can vary widely despite shared genetic causes. Mice deficient in Twisted gastrulation (Twsg1(-/-)) display such phenotypic variation, developing a wide range of craniofacial malformations on an isogenic C57BL/6 strain background. To examine the molecular basis for this reduced penetrance and variable expressivity, we used exon microarrays to analyze gene expression in mandibular arches from several distinct, morphologically defined classes of Twsg1(-/-) and wild type (WT) embryos. Hierarchical clustering analysis of transcript levels identified numerous differentially expressed genes, clearly distinguishing severely affected and unaffected Twsg1(-/-) mutants from WT embryos. Several genes that play well-known roles in craniofacial development were upregulated in unaffected Twsg1(-/-) mutant embryos, suggesting that they may compensate for the loss of TWSG1. Imprinted genes were overrepresented among genes that were differentially expressed particularly between affected and unaffected mutants. The most severely affected embryos demonstrated increased p53 signaling and increased expression of its target, Trp53inp1. The frequency of craniofacial defects significantly decreased with a reduction of p53 gene dosage from 44% in Twsg1(-/-)/p53(+/+) pups (N = 675) to 30% in Twsg1(-/-)p53(+/-) (N = 47, p=0.04) and 15% in Twsg1(-/-) littermates (N = 39, p = 0.001). In summary, these results demonstrate that phenotypic variability in Twsg1(-/-) mice is associated with differential expression of certain developmentally regulated genes, and that craniofacial defects can be partially rescued by reduced p53 levels. We postulate that variable responses to stress may contribute to variable craniofacial phenotypes by triggering differential expression of genes and variable cellular apoptosis. (C) 2011 Elsevier Inc. All rights reserved.