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Developmental CellFoxh1在前腦發(fā)育中的作用
點擊次數(shù)：767 發(fā)布時間：2014-2-4
前腦（forebrain）是人腦中zui復雜、zui重要的神經(jīng)中樞，它由視丘、下視丘、邊緣系統(tǒng)和大腦皮質四部分組成。雖然由簡單的神經(jīng)上皮發(fā)育而來，但其發(fā)育過程受到多種信號途徑的調控，包括β轉化生長因子（TGFβ）、成纖維細胞生長因子（FGFs)）、視黃酸等參與的信號通路。迄今為止，科學家對這些不同的信號分子之間如何相互作用，從而調控前腦的復雜結構仍然不甚明了。
Foxh1是一個DNA結合因子，它與Smad蛋白一起在生物早期發(fā)育過程中通過TGF-b信號通路調節(jié)蛋白質的表達。模式動物大鼠、小鼠、斑馬魚和蛙的實驗都證實Foxh1的缺失會導致動物早期發(fā)育的畸形。但是Foxh1具體怎樣實現(xiàn)這些生物學效應，目前并不*清楚。
在的研究中，加拿大多倫多大學和英國阿伯丁大學的研究人員開發(fā)出一種新的生物信息學的方法，把Smad/Foxh1功能性增強子系列制圖與定點查找結合起來，進行全基因組范圍的Foxh1靶蛋白搜索，并將搜索結果按照其在生物間的保守性打分分級。研究人員用該方法在模式生物及人的全基因組范圍共找到一百多個潛在的靶蛋白，其中主要的靶蛋白Aldh1a家族參與調節(jié)視黃酸的合成。在Foxh1缺失突變體中，Aldh1a家族幾個重要蛋白質不能表達，視黃酸響應因子也不能被激活。進一步的體內(nèi)和體外實驗證實Foxh1在胚胎發(fā)育過程中發(fā)揮了重要作用，并且通過啟動視黃酸合成信號來調節(jié)前腦的發(fā)育。
這一新的研究方法將有助于揭示胚胎發(fā)育早期的復雜轉錄因子網(wǎng)絡。該研究結果作為封面文章發(fā)表于2008年3月11日的《發(fā)育細胞》（Developmental Cell）上。
（Developmental Cell），Vol 14, 411-423, 11 March 2008，Cristoforo Silvestri, Liliana Attisano
genome-Wide Identification of Smad/Foxh1 Targets Reveals a Role for Foxh1 in Retinoic Acid Regulation and Forebrain Development
Cristoforo Silvestri,1,5 Masahiro Narimatsu,6 Ingo von Both,6 Yongmei Liu,6 Nicholas B.J. Tan,2 Luisa Izzi,3,5 Peter McCaffery,7 Jeffrey L. Wrana,4,6 and Liliana Attisano1,2,3,5,Developmental CellFoxh1在前腦發(fā)育中的作用
1 Institute of Medical science, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada
2 Department of Biochemistry, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada
3 Department of Medical Biophysics, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada
4 Department of Medical Genetics and Microbiology, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada
5 Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada
6 Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
7 Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom
Developmental CellFoxh1在前腦發(fā)育中的作用Corresponding author
Liliana Attisano
liliana.attisano@utoronto.ca
Summary
Foxh1, a Smad DNA-binding partner, mediates TGFβ-dependent gene expression during early development. Few Foxh1 targets are known. Here, we describe a genome-wide approach that we developed that couples systematic mapping of a functional Smad/Foxh1 enhancer (SFE) to Site Search, a program used to search annotated genomes for composite response elements. Ranking of SFEs that are positionally conserved across species yielded a set of genes enriched in Foxh1 targets. Analysis of top candidates, such as Hesx1, Lgr4, Lmo1, Fgf8, and members of the Aldh1a subfamily, revealed that Foxh1 initiates a transcriptional regulatory network within the developing anterior neuroectoderm. The Aldh1a family is required for retinoic acid (RA) synthesis, and, in Foxh1 mutants, expression of Aldh1a1, -2, and -3 and activation of a RA-responsive transgenic reporter is abolished in anterior structures. Integrated mapping of a developmental transcription factor network thus reveals a key role for Foxh1 in patterning and initiating RA signaling in the forebrain.