Differential requirement of SUFU in tissue development discovered in a hypomorphic mouse model.
Differential requirement of SUFU in tissue development discovered in a hypomorphic mouse model.
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Sufu在肌型小鼠模型中发现的组织发育中的差异需求。
DOI：
10.1016/j.ydbio.2017.06.037
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发表时间：
2017-09-01
影响因子：
2.7
通讯作者：
Teglund S
中科院分区：
文献类型：
--
作者：
Hoelzl MA;Heby-Henricson K;Gerling M;Dias JM;Kuiper RV;Trünkle C;Bergström Å;Ericson J;Toftgård R;Teglund S
融合抑制因子(SuFU)是Hedgehog(HH)途径的重要负调控因子，参与GLI转录因子的调控。由于Sufu−/−小鼠早期胚胎致死，对Sufu在发育后期的作用的研究仅限于条件性的、组织特异性的基因敲除模型。在这项研究中，我们开发了一种具有低形态特征的小鼠模型(SufuEx456(Fl)/Ex456(Fl))，其中胚胎可以存活到E18.5，尽管有一系列严重的发育缺陷，包括多指畸形、脑外畸形和脐膨出。某些组织的发育，如骨骼，比皮肤等其他组织受到的影响更大，皮肤基本上保持正常。有趣的是，在E9.0时，神经管的背腹模式没有明显的变化。因此，该模型为超越E9.5的SUFU在器官发生中的分子功能的全球研究提供了机会。在分子水平上，SufuEx456(Fl)/Ex456(Fl)胚胎在所有组织中均表现出异常的mRNA剪接，并显著降低Sufu野生型mRNA和SuFU蛋白的水平。因此，在E9.5，所有三种不同的GLI蛋白的水平都降低了。有趣的是，尽管GLI3蛋白水平降低，但与野生型胚胎相比，GLI3全长转录激活因子与GLI3截短阻遏因子的临界比率保持不变。这表明，目前存在的有限数量的SUFU蛋白质足以进行GLI加工，但不足以稳定。我们的数据表明，随着SUFU水平的降低，组织发育受到不同程度的影响，这为正确的器官发生提供了关于不同水平SUFU需求的新见解。
Suppressor of Fused (SUFU) is an essential negative regulator of the Hedgehog (HH) pathway and involved in GLI transcription factor regulation. Due to early embryonic lethality of Sufu−/− mice, investigations of SUFU’s role later in development are limited to conditional, tissue-specific knockout models. In this study we developed a mouse model (SufuEx456(fl)/Ex456(fl)) with hypomorphic features where embryos were viable up to E18.5, although with a spectrum of developmental defects of varying severity, including polydactyly, exencephaly and omphalocele. Development of certain tissues, like the skeleton, was more affected than that of others such as skin, which remained largely normal. Interestingly, no apparent changes in the dorso-ventral patterning of the neural tube at E9.0 could be seen. Thus, this model provides an opportunity to globally study SUFU’s molecular function in organogenesis beyond E9.5. Molecularly, SufuEx456(fl)/Ex456(fl) embryos displayed aberrant mRNA splicing and drastically reduced levels of Sufu wild-type mRNA and SUFU protein in all tissues. As a consequence, at E9.5 the levels of all three different GLI proteins were reduced. Interestingly, despite the reduction of GLI3 protein levels, the critical ratio of the GLI3 full-length transcriptional activator versus GLI3 truncated repressor remained unchanged compared to wild-type embryos. This suggests that the limited amount of SUFU protein present is sufficient for GLI processing but not for stabilization. Our data demonstrate that tissue development is differentially affected in response to the reduced SUFU levels, providing novel insight regarding the requirements of different levels of SUFU for proper organogenesis.
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影响因子：
--
作者：
Goetz, Sarah C.;Ocbina, Polloneal J. R.;Anderson, Kathryn V.
通讯作者：
Anderson, Kathryn V.
DOI：
10.1016/j.bbrc.2009.07.087
发表时间：
2009-09-25
影响因子：
3.1
作者：
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通讯作者：
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作者：
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通讯作者：
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影响因子：
2.7
作者：
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通讯作者：
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影响因子：
30.8
作者：
HUI, CC;JOYNER, AL
通讯作者：
JOYNER, AL