During midfacial morphogenesis in mice, we observed Frem1 expression in the embryonic growth centers that form the median upper lip, nose, and palate. Expansive spatial gradients of Frem1 expression in the cranial neural crest cell (cNCC) mesenchyme of these tissues suggested transcriptional regulation by a secreted morphogen. Accordingly, Frem1 expression paralleled that of the conserved Sonic Hedgehog (Shh) target gene Gli1 in the cNCC mesenchyme. Suggesting direct transcriptional regulation by Shh signaling, we found that Frem1 expression is induced by SHH ligand stimulation or downstream pathway activation in cNCCs and observed GLI transcription factor binding at the Frem1 transcriptional start site during midfacial morphogenesis. Finally, we found that FREM1 is sufficient to induce cNCC proliferation in a concentration-dependent manner and that Shh pathway antagonism reduces Frem1 expression during pathogenesis of midfacial hypoplasia.
By demonstrating that the Shh signaling pathway regulates Frem1 expression in cNCCs, these findings provide novel insight into the mechanisms underlying variation in midfacial morphogenesis.
结果:在小鼠中面部形态发生过程中,我们观察到Frem1在形成中部上唇的胚胎生长中心表达,鼻子,和味觉。这些组织的颅神经c细胞(cNCC)间充质中Frem1表达的扩展空间梯度表明了分泌的形态发生原的转录调节。因此,Frem1的表达与cNCC间充质中保守的SonicHedgehog(Shh)靶基因Gli1的表达平行。提示Shh信号的直接转录调控,我们发现Frem1的表达是由SHH配体刺激或cNCC下游途径激活诱导的,并且在面部中部形态发生过程中观察到GLI转录因子在Frem1转录起始位点的结合。最后,我们发现FREM1足以以浓度依赖性方式诱导cNCC增殖,而Shh通路拮抗作用在面部中部发育不全的发病过程中会降低Frem1的表达.
结论:通过证明Shh信号通路调节cNCCs中Frem1的表达,这些发现为面部中部形态发生变异的潜在机制提供了新的见解。本文受版权保护。保留所有权利。