Developmental Cell：Foxh1在前脑发育中的作用
前脑（forebrain）是人脑中最复杂、最重要的神经中枢，它由视丘、下视丘、边缘系统和大脑皮质四部分组成。虽然由简单的神经上皮发育而来，但其发育过程受到多种信号途径的调控，包括β转化生长因子（TGFβ）、成纤维细胞生长因子（FGFs)）、视黄酸等参与的信号通路。迄今为止，科学家对这些不同的信号分子之间如何相互作用，从而调控前脑的复杂结构仍然不甚明了。
Foxh1是一个DNA结合因子，它与Smad蛋白一起在生物早期发育过程中通过TGF-b信号通路调节蛋白质的表达。模式动物大鼠、小鼠、斑马鱼和蛙的实验都证实Foxh1的缺失会导致动物早期发育的畸形。但是Foxh1具体怎样实现这些生物学效应，目前并不完全清楚。
在最新的研究中，加拿大多伦多大学和英国阿伯丁大学的研究人员开发出一种新的生物信息学的方法，把Smad/Foxh1功能性增强子系列制图与定点查找结合起来，进行全基因组范围的Foxh1靶蛋白搜索，并将搜索结果按照其在生物间的保守性打分分级。研究人员用该方法在模式生物及人的全基因组范围共找到一百多个潜在的靶蛋白，其中主要的靶蛋白Aldh1a家族参与调节视黄酸的合成。在Foxh1缺失突变体中，Aldh1a家族几个重要蛋白质不能表达，视黄酸响应因子也不能被激活。进一步的体内和体外实验证实Foxh1在胚胎发育过程中发挥了重要作用，并且通过启动视黄酸合成信号来调节前脑的发育。
这一新的研究方法将有助于揭示胚胎发育早期的复杂转录因子网络。该研究结果作为封面文章发表于2008年3月11日的《发育细胞》（Developmental Cell）上。
生物谷推荐原始出处：
（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,
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
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.
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