Department of Orthopaedic Surgery, San Francisco General Hospital, University of California, San Francisco, San Francisco, California, USA.
The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Zhejiang University Life Sciences Institute, Hangzhou, China.
Dev Dyn. 2020 Sep;249(9):1062-1076. doi: 10.1002/dvdy.191. Epub 2020 Aug 4.
The frontonasal ectodermal zone (FEZ) is a signaling center that regulates patterned development of the upper jaw, and Sonic hedgehog (SHH) mediates FEZ activity. Induction of SHH expression in the FEZ results from SHH-dependent signals from the brain and neural crest cells. Given the role of miRNAs in modulating gene expression, we investigated the extent to which miRNAs regulate SHH expression and FEZ signaling.
In the FEZ, the miR-199 family appears to be regulated by SHH-dependent signals from the brain; expression of this family increased from HH18 to HH22, and upon activation of SHH signaling in the brain. However, the miR-199 family is more broadly expressed in the mesenchyme of the frontonasal process and adjacent neuroepithelium. Downregulating the miR-199 genes expanded SHH expression in the FEZ, resulting in wider faces, while upregulating miR-199 genes resulted in decreased SHH expression and narrow faces. Hypoxia inducible factor 1 alpha (HIF1A) and mitogen-activated protein kinase kinase kinase 4 (MAP3K4) appear to be potential targets of miR-199b. Reduction of MAP3K4 altered beak development but increased apoptosis, while reducing HIF1A reduced expression of SHH in the FEZ and produced malformations independent of apoptosis.
Our results demonstrate that this miRNA family appears to participate in regulating SHH expression in the FEZ; however, specific molecular mechanisms remain unknown.
额鼻外胚层区 (FEZ) 是一个信号中心，调节上颌的图案发育，而 Sonic 刺猬 (SHH) 介导 FEZ 活性。FEZ 中 SHH 表达的诱导来自大脑和神经嵴细胞的 SHH 依赖性信号。鉴于 miRNAs 在调节基因表达中的作用，我们研究了 miRNAs 调节 SHH 表达和 FEZ 信号的程度。
在 FEZ 中，miR-199 家族似乎受大脑中 SHH 依赖性信号的调节；从 HH18 到 HH22，该家族的表达增加，并且在大脑中激活 SHH 信号后增加。然而，miR-199 家族在额鼻突的间质和相邻神经上皮中更广泛地表达。下调 miR-199 基因可扩大 FEZ 中的 SHH 表达，导致面部变宽，而上调 miR-199 基因可导致 SHH 表达减少和面部变窄。缺氧诱导因子 1 阿尔法 (HIF1A) 和丝裂原活化蛋白激酶激酶激酶 4 (MAP3K4) 似乎是 miR-199b 的潜在靶点。MAP3K4 的减少改变了喙的发育但增加了细胞凋亡，而 HIF1A 的减少减少了 FEZ 中 SHH 的表达并产生了独立于细胞凋亡的畸形。
我们的结果表明，该 miRNA 家族似乎参与调节 FEZ 中的 SHH 表达；然而，具体的分子机制尚不清楚。
