Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, NY 10065, USA.
Dev Cell. 2011 Oct 18;21(4):627-41. doi: 10.1016/j.devcel.2011.08.005. Epub 2011 Oct 6.
Morphogenesis of mammalian facial processes requires coordination of cellular proliferation, migration, and apoptosis to develop intricate features. Cleft lip and/or palate (CL/P), the most frequent human craniofacial birth defect, can be caused by perturbation of any of these programs. Mutations of WNT, P63, and IRF6 yield CL/P in humans and mice; however, how these genes are regulated remains elusive. We generated mouse lines lacking Pbx genes in cephalic ectoderm and demonstrated that they exhibit fully penetrant CL/P and perturbed Wnt signaling. We also characterized a midfacial regulatory element that Pbx proteins bind to control the expression of Wnt9b-Wnt3, which in turn regulates p63. Altogether, we establish a Pbx-dependent Wnt-p63-Irf6 regulatory module in midfacial ectoderm that is conserved within mammals. Dysregulation of this network leads to localized suppression of midfacial apoptosis and CL/P. Ectopic Wnt ectodermal expression in Pbx mutants rescues the clefting, opening avenues for tissue repair.
哺乳动物面部过程的形态发生需要细胞增殖、迁移和凋亡的协调，以形成复杂的特征。唇裂和/或腭裂（CL/P）是最常见的人类颅面出生缺陷，可能是由于这些程序中的任何一个受到干扰而导致的。WNT、P63 和 IRF6 的突变会导致人类和小鼠出现 CL/P；然而，这些基因是如何被调控的仍然难以捉摸。我们生成了头部外胚层中缺乏 PBX 基因的小鼠品系，并证明它们表现出完全穿透性的 CL/P 和 Wnt 信号的扰动。我们还描述了一个中面部调控元件，PBX 蛋白与之结合，控制 Wnt9b-Wnt3 的表达，进而调控 p63。总的来说，我们在中面部外胚层中建立了一个依赖 PBX 的 Wnt-p63-Irf6 调控模块，在哺乳动物中是保守的。该网络的失调会导致中面部细胞凋亡的局部抑制和 CL/P。在 PBX 突变体中外胚层表达异位 Wnt 可以挽救裂隙，为组织修复开辟途径。
