Salivary gland branching morphogenesis: a quantitative systems analysis of the Eda/Edar/NFkappaB paradigm.
Salivary gland branching morphogenesis: a quantitative systems analysis of the Eda/Edar/NFkappaB paradigm.
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DOI：
10.1186/1471-213x-9-32
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发表时间：
2009-06-06
影响因子：
--
通讯作者：
Jaskoll T
中科院分区：
文献类型：
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作者：
Melnick M;Phair RD;Lapidot SA;Jaskoll T
外胚层发育不良-A似乎是分支形态发生的关键组成部分。小鼠EDA或人EDA中的突变与汗腺、皮脂腺、泪腺、唾液腺（SMG）、乳腺和/或乳头以及支气管、食管和结肠粘膜的粘液腺缺失或发育不全相关。在这项研究中，我们利用EdaTa（Tabby）突变小鼠来研究功能性Eda的显着减少如何通过定义的遗传子回路随时间传播，并测试经典NF κ B信号传导足以解释Eda多态性背景下发育调节基因的差异表达的命题。定量系统分析不支持所述假设。对于大多数NF κ B调节的基因，与野生型小鼠相比，在Tabby（EdaTa）中观察到的基因表达的时间过程几乎没有变化，NF κ B本身也是如此。重要的是，一组基因在虎斑猫中显著差异表达（Edar、Fgf8、Shh、Egf、Tgfa、Egfr），这强烈表明存在对SMG个体发育至关重要的另一种Eda介导的转录途径。实验和计算机模拟研究已将C/EBP α确定为有希望的候选物。在Tabby SMG中，Egf/Tgf α/Egfr通路的上调似乎减轻了Fgf 8和Shh下调预测的潜在重度异常表型。其他人已经提出，与变体Eda信号传导一致的表型结果的缓冲可能是允许正常和异常的可行的和多样的表型的常见机制。我们的结果支持这一主张。此外，如果分支上皮细胞使用典型的发展计划的变化，我们的研究结果可能适用于了解受EDA（EDA）突变影响的其他分支器官的表型。
Ectodysplasin-A appears to be a critical component of branching morphogenesis. Mutations in mouse Eda or human EDA are associated with absent or hypoplastic sweat glands, sebaceous glands, lacrimal glands, salivary glands (SMGs), mammary glands and/or nipples, and mucous glands of the bronchial, esophageal and colonic mucosa. In this study, we utilized EdaTa (Tabby) mutant mice to investigate how a marked reduction in functional Eda propagates with time through a defined genetic subcircuit and to test the proposition that canonical NFκB signaling is sufficient to account for the differential expression of developmentally regulated genes in the context of Eda polymorphism. The quantitative systems analyses do not support the stated hypothesis. For most NFκB-regulated genes, the observed time course of gene expression is nearly unchanged in Tabby (EdaTa) as compared to wildtype mice, as is NFκB itself. Importantly, a subset of genes is dramatically differentially expressed in Tabby (Edar, Fgf8, Shh, Egf, Tgfa, Egfr), strongly suggesting the existence of an alternative Eda-mediated transcriptional pathway pivotal for SMG ontogeny. Experimental and in silico investigations have identified C/EBPα as a promising candidate. In Tabby SMGs, upregulation of the Egf/Tgfα/Egfr pathway appears to mitigate the potentially severe abnormal phenotype predicted by the downregulation of Fgf8 and Shh. Others have suggested that the buffering of the phenotypic outcome that is coincident with variant Eda signaling could be a common mechanism that permits viable and diverse phenotypes, normal and abnormal. Our results support this proposition. Further, if branching epithelia use variations of a canonical developmental program, our results are likely applicable to understanding the phenotypes of other branching organs affected by Eda (EDA) mutation.