The level of BMP4 signaling is critical for the regulation of distinct T-box gene expression domains and growth along the dorso-ventral axis of the optic cup.
The level of BMP4 signaling is critical for the regulation of distinct T-box gene expression domains and growth along the dorso-ventral axis of the optic cup.
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DOI：
10.1186/1471-213x-6-62
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发表时间：
2006-12-15
影响因子：
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通讯作者：
Sowden JC
中科院分区：
文献类型：
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作者：
Behesti H;Holt JK;Sowden JC
极化的基因表达被认为导致信号分子的分级分布，从而在整个胚胎眼睛中提供了一种图案化机制。骨形态发生蛋白4(Bmp4)在转化为视杯的背侧视泡中表达。BMP4在人类和小鼠中的缺失导致眼睛发育失败，但很少有人尝试研究BMP4信号的哺乳动物靶标。在鸡中，逆转录病毒基因过表达的研究表明，Bmp4激活了背部表达的Tbx5基因，该基因抑制了腹向表达的cVax。目前尚不清楚Tbx5相关基因Tbx2和Tbx3是否是哺乳动物视网膜中的BMP4靶标，以及BMP4是否在距离其表达部位很远的地方起作用。虽然已经确定果蝇DPP(脊椎动物Bmp4的同源物)作为一种形态发生因子，但很少有证据表明BMP4梯度被解释为在小鼠中创建了BMP4靶基因表达的区域。我们的数据表明，BMP4信号的水平对于小鼠视杯背腹轴上不同的Tbx2、Tbx3、Tbx5和Vax2基因表达域的调节至关重要。在视杯发育过程中，通过植入浸泡在BMP4中的珠子或BMP拮抗剂Noggin，在整个小鼠胚胎培养中操纵BMP4信号梯度，以提供局部信号源。Tbx2、Tbx3和Tbx5对视杯背腹轴BMP4水平的改变表现出不同的反应，表明BMP4的作用跨越了距离。BMP4水平的增加导致Tbx2和Tbx3扩张到腹侧视网膜，而不是Tbx5，并抑制腹侧标记Vax2。相反，Noggin取消了Tbx5的表达，但只移动了Tbx2的表达。BMP4信号水平的增加导致增殖减少，视网膜体积减少，并改变了视杯的形状。我们的发现表明，BMP4信号存在背侧高、腹侧低的信号梯度，Tbx2、Tbx3、Tbx5和Vax2转录因子基因表达的不同区域在这个梯度上存在。此外，我们还发现，BMP4信号的正确水平对于哺乳动物胚胎眼睛的正常生长至关重要。
Polarised gene expression is thought to lead to the graded distribution of signaling molecules providing a patterning mechanism across the embryonic eye. Bone morphogenetic protein 4 (Bmp4) is expressed in the dorsal optic vesicle as it transforms into the optic cup. Bmp4 deletions in human and mouse result in failure of eye development, but little attempt has been made to investigate mammalian targets of BMP4 signaling. In chick, retroviral gene overexpression studies indicate that Bmp4 activates the dorsally expressed Tbx5 gene, which represses ventrally expressed cVax. It is not known whether the Tbx5 related genes, Tbx2 and Tbx3, are BMP4 targets in the mammalian retina and whether BMP4 acts at a distance from its site of expression. Although it is established that Drosophila Dpp (homologue of vertebrate Bmp4) acts as a morphogen, there is little evidence that BMP4 gradients are interpreted to create domains of BMP4 target gene expression in the mouse. Our data show that the level of BMP4 signaling is critical for the regulation of distinct Tbx2, Tbx3, Tbx5 and Vax2 gene expression domains along the dorso-ventral axis of the mouse optic cup. BMP4 signaling gradients were manipulated in whole mouse embryo cultures during optic cup development, by implantation of beads soaked in BMP4, or the BMP antagonist Noggin, to provide a local signaling source. Tbx2, Tbx3 and Tbx5, showed a differential response to alterations in the level of BMP4 along the entire dorso-ventral axis of the optic cup, suggesting that BMP4 acts across a distance. Increased levels of BMP4 caused expansion of Tbx2 and Tbx3, but not Tbx5, into the ventral retina and repression of the ventral marker Vax2. Conversely, Noggin abolished Tbx5 expression but only shifted Tbx2 expression dorsally. Increased levels of BMP4 signaling caused decreased proliferation, reduced retinal volume and altered the shape of the optic cup. Our findings suggest the existence of a dorsal-high, ventral-low BMP4 signaling gradient across which distinct domains of Tbx2, Tbx3, Tbx5 and Vax2 transcription factor gene expression are set up. Furthermore we show that the correct level of BMP4 signaling is critical for normal growth of the mammalian embryonic eye.