Fgf8b-containing spliceforms, but not Fgf8a, are essential for Fgf8 function during development of the midbrain and cerebellum.
Fgf8b-containing spliceforms, but not Fgf8a, are essential for Fgf8 function during development of the midbrain and cerebellum.
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DOI：
10.1016/j.ydbio.2009.11.034
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发表时间：
2010-02-15
影响因子：
2.7
通讯作者：
Li, James Y. H.
中科院分区：
文献类型：
--
作者：
Guo, Qiuxia;Li, Kairong;Sunmonu, N. Abimbola;Li, James Y. H.
Fgf8基因在小鼠体内通过选择性剪接产生8种N端不同的蛋白质异构体（Fgf8a-h）。功能获得性研究已经证明，Fgf8a和Fgf8b在发育中的中脑和后脑（MHB）中具有不同的活性，这是由于它们与FGF受体的不同结合亲和力。在这里，我们进行了功能丧失分析，以确定在MHB开发过程中这两种Fgf8剪接形式的体内需求。我们发现，缺失Fgf 8 b的剪接形式（B，d，f和h）导致MHB区域中多个关键调控基因的丢失，包括Fgf 8本身。因此，在MHB祖细胞中，含Fgf8b的剪接形式的特异性失活（类似于Fgf8的丢失）导致中脑、峡部和小脑的缺失。我们还创建了一个剪接位点突变，消除了含有Fgf8a的剪接形式（a，c，e和g）。缺乏含Fgf8a剪接形式的小鼠表现出生长迟缓和出生后致死性，并且表型在不同遗传背景中是可变的，这表明含Fgf8a剪接形式可能在调节Fgf8活性中起作用。令人惊讶的是，在Fgf8a缺陷小鼠的中脑和小脑中没有检测到可辨别的缺陷。为了确定基于功能获得性研究在MHB区域中表达并且具有与Fgf8a相似的活性的Fgf17是否可以补偿Fgf8a的损失，我们产生了Fgf17和Fgf8a双突变小鼠。缺乏Fgf8a剪接形式和Fgf17的小鼠在中脑后部和小脑前部显示出与Fgf17突变小鼠相同的缺陷。因此，在中脑和小脑的发育过程中，含有Fgf8b的剪接形式，而不是Fgf8a，对Fgf8的功能是必不可少的。
The single Fgf8 gene in mice produces eight protein isoforms (Fgf8a–h) with different N-termini by alternative splicing. Gain-of-function studies have demonstrated that Fgf8a and Fgf8b have distinct activities in the developing midbrain and hindbrain (MHB) due to their different binding affinities with FGF receptors. Here we have performed loss-of-function analyses to determine the in vivo requirement for these two Fgf8 spliceforms during MHB development. We showed that deletion of Fgf8b-containing spliceforms (b, d, f and h) leads to loss of multiple key regulatory genes, including Fgf8 itself, in the MHB region. Therefore, specific inactivation of Fgf8b-containing spliceforms, similar to the loss of Fgf8, in MHB progenitors results in deletion of the midbrain, isthmus, and cerebellum. We also created a splice-site mutation abolishing Fgf8a-containing spliceforms (a, c, e, and g). Mice lacking Fgf8a-containing spliceforms exhibit growth retardation and postnatal lethality, and the phenotype is variable in different genetic backgrounds, suggesting that the Fgf8a-containing spliceforms may play a role in modulating the activity of Fgf8. Surprisingly, no discernable defect was detected in the midbrain and cerebellum of Fgf8a-deficient mice. To determine if Fgf17, which is expressed in the MHB region and possesses similar activities to Fgf8a based on gain-of-function studies, may compensate for the loss of Fgf8a, we generated Fgf17 and Fgf8a double mutant mice. Mice lacking both Fgf8a-containing spliceforms and Fgf17 display the same defect in the posterior midbrain and anterior cerebellum as Fgf17 mutant mice. Therefore, Fgf8b-containing spliceforms, but not Fgf8a, are essential for the function of Fgf8 during the development of the midbrain and cerebellum.
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影响因子：
16.2
作者：
Li, JYH;Lao, ZM;Joyner, AL
通讯作者：
Joyner, AL
DOI：
10.1242/dev.026229
发表时间：
2008-12
期刊：
Development (Cambridge, England)
影响因子：
--
作者：
Hong CS;Park BY;Saint-Jeannet JP
通讯作者：
Saint-Jeannet JP
影响因子：
2.6
作者：
Gogoi, RN;Schubert, FR;Lumsden, A
通讯作者：
Lumsden, A
影响因子：
2.6
作者：
Ohtoshi, A;Nishijima, I;Behringer, RR
通讯作者：
Behringer, RR
影响因子：
30.8
作者：
Meyers, EN;Lewandoski, M;Martin, GR
通讯作者：
Martin, GR