Division of Developmental Neurobiology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
Mech Dev. 2011 Jan-Feb;128(1-2):90-103. doi: 10.1016/j.mod.2010.11.002. Epub 2010 Nov 17.
Foxa2, a member of the Foxa family of forkhead/winged helix family of transcription factors, has previously been shown to be an upstream positive regulator of Shh expression in many different tissues. Recent studies also strongly suggest that Foxa2 specify cell fate by inhibiting the expression of cell fate determinants such as Helt1 and Nkx2.2. In this paper, phenotypic analyses of Wnt1cre; Foxa2flox/flox embryos in the midbrain have demonstrated a novel role for Foxa2 and its related family member, Foxa1, to attenuate Shh signalling by inhibiting the expression of its intracellular transducer, Gli2, at the transcriptional level. Chromatin immunoprecipitation experiments indicate that Foxa2 binds to genomic regions of Gli2 and likely regulates its expression in a direct manner. Our studies, involving loss and gain of function studies in mice, also provided further insights into the gene regulatory interactions among Foxa1, Foxa2 and Shh in ventral midbrain progenitors that contribute to midbrain patterning. Altogether, these data indicate that Foxa1 and Foxa2 contribute to the specification of ventral midbrain progenitor identity by regulating Shh signalling in a positive and negative manner.
叉头框蛋白 A2（Foxa2）是叉头框/翼状螺旋转录因子 Foxa 家族的成员，先前的研究表明，它是许多不同组织中 Shh 表达的上游正调控因子。最近的研究也强烈表明，Foxa2 通过抑制细胞命运决定因子（如 Helt1 和 Nkx2.2）的表达来决定细胞命运。在本文中，对中脑 Wnt1cre; Foxa2flox/flox 胚胎的表型分析表明，Foxa2 和其相关家族成员 Foxa1 通过在转录水平上抑制其细胞内转导子 Gli2 的表达，来减弱 Shh 信号。染色质免疫沉淀实验表明 Foxa2 结合到 Gli2 的基因组区域，并可能以直接方式调节其表达。我们的研究，包括在小鼠中进行的功能丧失和获得功能研究，还进一步深入了解了 Foxa1、Foxa2 和 Shh 之间在参与中脑模式形成的腹侧中脑神经祖细胞中的基因调控相互作用。总之，这些数据表明 Foxa1 和 Foxa2 通过正向和负向调节 Shh 信号来促进腹侧中脑神经祖细胞身份的特化。
