Sommer Paula, Napier Hugh R, Hogan Brigid L, Kidson Susan H
Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Observatory, South Africa.
Dev Growth Differ. 2006 Jun;48(5):297-308. doi: 10.1111/j.1440-169X.2006.00866.x.
Craniofacial development is severely affected by null mutations in Foxc1, indicating a multifunctional role for Foxc1 in ocular, maxilla and mandible, skull and facial gland development. To delineate signaling pathways in which Foxc1 is involved we compared the transcriptomes of whole heads of Foxc1+/+ and Foxc1-/- embryos using a candidate cDNA array comprising genes expressed in the head mesenchyme and ocular region, and a 7K oligo array. Absence of Foxc1 led to downregulation of Stat1 and Galnt4, and upregulation of Tgf beta1i4 at embryonic day 13.5 in the developing head mesenchyme. Comparative analyses revealed differences in the expression pattern of Tgf beta1i4 in the head mesenchyme of Foxc1-/- and Foxc1+/+ embryos. In the ocular regions of Foxc1-/- embryos, Tgf beta1i4 was expressed in higher levels in the conjunctival epithelium and in the condensing mesenchyme on the nasal aspect of the developing eye while in wild-type embryos more intense expression was seen in the mesenchyme on the temporal aspect of the eye. Such data indicate that Foxc1 regulation of Tgf beta1i4 is complex and may be cell-type dependent. Analysis of the regulation of Tgf beta1i4 by Foxc1 in a more homogenous cell population, mesenchymal cells isolated from the periocular region revealed that, in these cells, Foxc1 negatively regulated Tgf beta1i4 expression, presumably via secreted factors such as TGF-beta1. Since Foxc1 expression is essential for normal craniofacial development, it is possible that its downstream targets play a role in the development of the phenotypes associated with null mutations in Foxc1.
Foxc1基因的无效突变会严重影响颅面发育，这表明Foxc1在眼部、上颌骨和下颌骨、颅骨以及面部腺体发育中具有多功能作用。为了描绘Foxc1所涉及的信号通路，我们使用了一个包含在头部间充质和眼部区域表达的基因的候选cDNA阵列以及一个7K寡核苷酸阵列，比较了Foxc1+/+和Foxc1-/-胚胎全头部的转录组。在胚胎发育第13.5天，发育中的头部间充质中Foxc1的缺失导致Stat1和Galnt4的下调以及Tgf beta1i4的上调。比较分析揭示了Foxc1-/-和Foxc1+/+胚胎头部间充质中Tgf beta1i4表达模式的差异。在Foxc1-/-胚胎的眼部区域，Tgf beta1i4在结膜上皮以及发育中眼睛鼻侧的凝聚间充质中表达水平较高，而在野生型胚胎中，在眼睛颞侧的间充质中观察到更强的表达。这些数据表明Foxc1对Tgf beta1i4的调控是复杂的，可能依赖于细胞类型。在一个更均匀的细胞群体——从眼周区域分离的间充质细胞中分析Foxc1对Tgf beta1i4的调控，结果显示，在这些细胞中，Foxc1可能通过诸如TGF-beta1等分泌因子负向调控Tgf beta1i4的表达。由于Foxc1的表达对于正常颅面发育至关重要，其下游靶点有可能在与Foxc1无效突变相关的表型发育中发挥作用。
