Sharpening of expression domains induced by transcription and microRNA regulation within a spatio-temporal model of mid-hindbrain boundary formation.
Sharpening of expression domains induced by transcription and microRNA regulation within a spatio-temporal model of mid-hindbrain boundary formation.
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DOI：
10.1186/1752-0509-7-48
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发表时间：
2013-06-25
影响因子：
--
通讯作者：
Theis FJ
中科院分区：
文献类型：
--
作者：
Hock S;Ng YK;Hasenauer J;Wittmann D;Lutter D;Trümbach D;Wurst W;Prakash N;Theis FJ
在脊椎动物中，中后脑区域的建立是由峡部组织者介导的，峡部组织者是一种胚胎次级组织者，其特征在于具有明确界限的局部限制性基因表达结构域的明确模式。虽然峡部组织者在中脑-后脑边界的功能已经进行了广泛的实验研究，但仍不清楚这种明确的空间基因表达模式是如何在脊椎动物发育过程中建立的，这种空间基因表达模式对峡部组织者的功能至关重要。由于分泌的Wnt 1蛋白在峡部组织者功能中起着重要作用，因此我们特别关注Wnt 1基因表达的改进。我们分析了相应的小鼠基因调控网络的动态和相关的，扩散信号蛋白使用宏观模型的生物双尺度信号过程。尽管尖锐的基因表达域边界所产生的不连续性，我们证明了存在唯一的，正解的偏微分方程系统。这使得能够对表达模式的形成和稳定性进行数值和分析分析。值得注意的是，Wnt 1的计算表达域与实验证据相比没有明显的边界。随后，我们提出了一个转录后调节机制Wnt 1的小RNA产生观察到的尖锐的表达域边界。我们建立了一个候选miRNAs的列表，并通过放射性原位杂交证实了它们的表达模式。miRNA miR-709被鉴定为Wnt 1 mRNA的潜在调节因子，其通过荧光素酶传感器测定被验证。总之，我们对中脑-后脑边界基因表达模式诱导的理论分析表明，需要通过额外的Wnt 1调节来扩展模型。所开发的宏观模型的两个尺度的过程中促进其他形态的图案化过程的严格分析。
The establishment of the mid-hindbrain region in vertebrates is mediated by the isthmic organizer, an embryonic secondary organizer characterized by a well-defined pattern of locally restricted gene expression domains with sharply delimited boundaries. While the function of the isthmic organizer at the mid-hindbrain boundary has been subject to extensive experimental studies, it remains unclear how this well-defined spatial gene expression pattern, which is essential for proper isthmic organizer function, is established during vertebrate development. Because the secreted Wnt1 protein plays a prominent role in isthmic organizer function, we focused in particular on the refinement of Wnt1 gene expression in this context. We analyzed the dynamics of the corresponding murine gene regulatory network and the related, diffusive signaling proteins using a macroscopic model for the biological two-scale signaling process. Despite the discontinuity arising from the sharp gene expression domain boundaries, we proved the existence of unique, positive solutions for the partial differential equation system. This enabled the numerically and analytically analysis of the formation and stability of the expression pattern. Notably, the calculated expression domain of Wnt1 has no sharp boundary in contrast to experimental evidence. We subsequently propose a post-transcriptional regulatory mechanism for Wnt1 miRNAs which yields the observed sharp expression domain boundaries. We established a list of candidate miRNAs and confirmed their expression pattern by radioactive in situ hybridization. The miRNA miR-709 was identified as a potential regulator of Wnt1 mRNA, which was validated by luciferase sensor assays. In summary, our theoretical analysis of the gene expression pattern induction at the mid-hindbrain boundary revealed the need to extend the model by an additional Wnt1 regulation. The developed macroscopic model of a two-scale process facilitate the stringent analysis of other morphogen-based patterning processes.
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通过间隙基因交叉调节，基因表达在果蝇芽孢杆菌中进行了渠道化。
影响因子：
9.8
作者：
Manu;Surkova S;Spirov AV;Gursky VV;Janssens H;Kim AR;Radulescu O;Vanario-Alonso CE;Sharp DH;Samsonova M;Reinitz J
通讯作者：
Reinitz J
Mirbase：MicroRNA基因组学的工具。
影响因子：
14.9
作者：
Griffiths-Jones, Sam;Saini, Harpreet Kaur;van Dongen, Stijn;Enright, Anton J.
通讯作者：
Enright, Anton J.
DOI：
10.1126/science.1215691
发表时间：
2012-04-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Djuranovic S;Nahvi A;Green R
通讯作者：
Green R
影响因子：
30.8
作者：
Krek, A;Grun, D;Rajewsky, N
通讯作者：
Rajewsky, N
DOI：
10.1126/science.1215704
发表时间：
2012-04-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bazzini AA;Lee MT;Giraldez AJ
通讯作者：
Giraldez AJ