cAMP response element binding protein is required for differentiation of respiratory epithelium during murine development.
cAMP response element binding protein is required for differentiation of respiratory epithelium during murine development.
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DOI：
10.1371/journal.pone.0017843
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发表时间：
2011-03-08
期刊：
影响因子：
3.7
通讯作者：
Cole TJ
中科院分区：
文献类型：
--
作者：
Bird AD;Flecknoe SJ;Tan KH;Olsson PF;Antony N;Mantamadiotis T;Mollard R;Hooper SB;Cole TJ
cAMP反应元件结合蛋白1 （Creb1）转录因子在细胞内cAMP水平升高时调节细胞基因表达。Creb1 - / -胎鼠在表型上比野生型仔鼠小，主要在子宫内死亡，出生后由于呼吸衰竭而无法存活。我们进一步研究了Creb1−/−胎儿小鼠在发育过程中的呼吸缺陷。Creb1−/−胎鼠的肺颜色苍白，与野生型对照相比，肺的大小与它们缩小的体型成比例。在E16.5之后，Creb1 - / -肺在形态上也不成熟，气道腔空间很少或没有扩张，在Crem - / -遗传背景下，Creb1 - / -肺也观察到这种表型。在检查的所有阶段，Creb1在整个肺中都高度表达，然而，Creb1的激活主要在远端肺上皮中检测到。电镜观察E17.5 Creb1−/−肺远端上皮细胞分化情况，发现i型和ii型肺泡上皮细胞数量明显减少。此外，包括纤毛细胞、非纤毛细胞（Clara）和神经内分泌细胞在内的近端上皮特定谱系的免疫标记物在Creb1−/−肺中的表达延迟。最后，利用全基因组芯片和qPCR对E17.5 Creb1−/−肺进行基因表达分析，共同鉴定呼吸标记基因谱，并提供潜在的新型Creb1调控基因。总之，这些结果表明Creb1活性在传导和远端肺上皮的发育和分化中起着至关重要的作用。
The cAMP response element binding protein 1 (Creb1) transcription factor regulates cellular gene expression in response to elevated levels of intracellular cAMP. Creb1 −/− fetal mice are phenotypically smaller than wildtype littermates, predominantly die in utero and do not survive after birth due to respiratory failure. We have further investigated the respiratory defect of Creb1−/− fetal mice during development. Lungs of Creb1−/− fetal mice were pale in colour and smaller than wildtype controls in proportion to their reduced body size. Creb1−/− lungs also did not mature morphologically beyond E16.5 with little or no expansion of airway luminal spaces, a phenotype also observed with the Creb1−/− lung on a Crem −/− genetic background. Creb1 was highly expressed throughout the lung at all stages examined, however activation of Creb1 was detected primarily in distal lung epithelium. Cell differentiation of E17.5 Creb1 −/− lung distal epithelium was analysed by electron microscopy and showed markedly reduced numbers of type-I and type-II alveolar epithelial cells. Furthermore, immunomarkers for specific lineages of proximal epithelium including ciliated, non-ciliated (Clara), and neuroendocrine cells showed delayed onset of expression in the Creb1−/− lung. Finally, gene expression analyses of the E17.5 Creb1 −/− lung using whole genome microarray and qPCR collectively identified respiratory marker gene profiles and provide potential novel Creb1-regulated genes. Together, these results demonstrate a crucial role for Creb1 activity for the development and differentiation of the conducting and distal lung epithelium.
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影响因子：
4.8
作者：
Davé, V;Childs, T;Whitsett, JA
通讯作者：
Whitsett, JA
影响因子：
--
作者：
ALCORN, DG;ADAMSON, TM;ROBINSON, PM
通讯作者：
ROBINSON, PM
影响因子：
5.3
作者：
Bleckmann, SC;Blendy, JA;Schütz, G
通讯作者：
Schütz, G
DOI：
10.1073/pnas.91.12.5647
发表时间：
1994-06-07
影响因子：
11.1
作者：
HUMMLER, E;COLE, TJ;SCHUTZ, G
通讯作者：
SCHUTZ, G
影响因子：
4.8
作者：
He, YC;Crouch, E
通讯作者：
Crouch, E