Lmx1a encodes a rostral set of mesodiencephalic dopaminergic neurons marked by the Wnt/B-catenin signaling activator R-spondin 2.
Lmx1a encodes a rostral set of mesodiencephalic dopaminergic neurons marked by the Wnt/B-catenin signaling activator R-spondin 2.
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DOI：
10.1371/journal.pone.0074049
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Smidt MP
中科院分区：
文献类型：
--
作者：
Hoekstra EJ;von Oerthel L;van der Heide LP;Kouwenhoven WM;Veenvliet JV;Wever I;Jin YR;Yoon JK;van der Linden AJ;Holstege FC;Groot Koerkamp MJ;Smidt MP
最近的事态发展中间脑多巴胺能（mdDA）神经元的分子编程导致许多转录因子的识别发挥作用的mdDA规范。LIM同源结构域转录因子Lmx 1a对鸡mdDA发育和ES细胞向多巴胺能表型的有效分化至关重要。在这项研究中，我们的目的是通过基因表达谱更详细地了解Lmx 1a缺陷（dreher）小鼠的微妙表型。进行转录组分析，以阐明Lmx 1a缺失后神经元缺陷的确切分子编程。随后对脑切片的表达分析证实Nurr 1受Lmx 1a调控，并鉴定了其他下游靶点，如Pou 4f 1、Pbx 1、Pitx 2、C130021 l20 Rik、Calb 2和Rspo 2。在一个特定的，吻侧（前体2/3）的表达损失的大部分这些基因在发展过程中，Nurr 1和C130021 l20 Rik的成熟mdDA系统的SNc的影响。有趣的是，这种缺陷的标志是Wnt/b-连环蛋白信号传导激活剂Rspo 2在该结构域中的完全丧失。随后对Rspo 2 −/−胚胎的分析显示，mdDA神经元受到影响，部分表现为Lmx 1a突变体。总之，我们的研究表明，Lmx 1a是必不可少的嘴侧亚组的mdDA神经元领域，在那里它可能通过调节Wnt激活剂Rspo 2的调节mdDA祖细胞的增殖和分化的关键功能。
Recent developments in molecular programming of mesodiencephalic dopaminergic (mdDA) neurons have led to the identification of many transcription factors playing a role in mdDA specification. LIM homeodomain transcription factor Lmx1a is essential for chick mdDA development, and for the efficient differentiation of ES-cells towards a dopaminergic phenotype. In this study, we aimed towards a more detailed understanding of the subtle phenotype in Lmx1a-deficient (dreher) mice, by means of gene expression profiling. Transcriptome analysis was performed, to elucidate the exact molecular programming underlying the neuronal deficits after loss of Lmx1a. Subsequent expression analysis on brain sections, confirmed that Nurr1 is regulated by Lmx1a, and additional downstream targets were identified, like Pou4f1, Pbx1, Pitx2, C130021l20Rik, Calb2 and Rspo2. In line with a specific, rostral-lateral (prosomer 2/3) loss of expression of most of these genes during development, Nurr1 and C130021l20Rik were affected in the SNc of the mature mdDA system. Interestingly, this deficit was marked by the complete loss of the Wnt/b-catenin signaling activator Rspo2 in this domain. Subsequent analysis of Rspo2−/− embryos revealed affected mdDA neurons, partially phenocopying the Lmx1a mutant. To conclude, our study revealed that Lmx1a is essential for a rostral-lateral subset of the mdDA neuronal field, where it might serve a critical function in modulating proliferation and differentiation of mdDA progenitors through the regulation of the Wnt activator Rspo2.
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DOI：
10.1073/pnas.0902396106
发表时间：
2009-05-05
影响因子：
11.1
作者：
Friling, Stina;Andersson, Elisabet;Ericson, Johan
通讯作者：
Ericson, Johan
影响因子：
4.6
作者：
Bell, Sheila M.;Schreiner, Claire M.;Whitsett, Jeffrey A.
通讯作者：
Whitsett, Jeffrey A.
影响因子：
3.3
作者：
Kim, Kyung-Ah;Wagle, Marie;Abo, Arie
通讯作者：
Abo, Arie
影响因子：
4.3
作者：
Kim, KA;Zhao, JS;Funk, WD
通讯作者：
Funk, WD
影响因子：
2.5
作者：
Chizhikov, Victor;Steshina, Ekaterina;Millen, Kathleen J.
通讯作者：
Millen, Kathleen J.