Pbx loss in cranial neural crest, unlike in epithelium, results in cleft palate only and a broader midface.
Pbx loss in cranial neural crest, unlike in epithelium, results in cleft palate only and a broader midface.
复制标题
DOI：
10.1111/joa.12821
复制
发表时间：
2018-08
影响因子：
2.4
通讯作者：
Selleri L
中科院分区：
文献类型：
--
作者：
Welsh IC;Hart J;Brown JM;Hansen K;Rocha Marques M;Aho RJ;Grishina I;Hurtado R;Herzlinger D;Ferretti E;Garcia-Garcia MJ;Selleri L
颅面裂是最常见的颅面先天性缺陷。唇裂伴或不伴腭裂（CL/P）与单纯腭裂（CPO）在基因上是不同的。许多转录因子（TFs）通过控制基本的细胞行为来调节包括前颌骨、上颌骨和腭骨在内的中面部的正常发育。在Pbx基因家族中，我们先前已经在小鼠中发现，Pbx1在面中形态发生中起着重要作用，而Pbx2和Pbx3在共表达域中发挥协同作用。我们还报道，在Pbx2‐或Pbx3‐缺乏的背景下，Pbx1从头上皮结构域丢失，通过破坏控制额鼻和上颌突融合缝凋亡的调节网络导致CL/P。相反，在Pbx2缺乏的背景下，颅神经嵴细胞（CNCC）衍生的间质中Pbx1的缺失会导致CPO，这是一种尚未表征的表型。在这项研究中，我们深入分析了PBX1和PBX2蛋白的定位，从面中形态发生的早期阶段开始，一直持续到第二腭的发育。我们进一步确定了PBX TFs在CNCC中的特定作用，并描述了它们在小鼠胚胎次腭中缺失所导致的发育异常。此外，我们比较和对比了CNCC中PBX1缺失与上皮中PBX1缺失引起的表型，并表明CNCC特异性PBX1缺失仅影响后来的继发腭形态发生。此外，CNCC突变体表现出背尾部组织紊乱和面中复合体变宽。增殖缺陷在妊娠期的CNCC突变体中很明显(E)12.5，提示突变腭祖细胞增殖发生改变，与PBX因子在维持祖细胞状态中的作用一致。虽然CNCC突变体的颅面骨骼异常不是由明显的模式缺陷引起的，但成骨延迟，强调了PBX因子在CNCC形态发生和分化中的关键作用。总的来说，组织特异性Pbx功能丧失小鼠模型的特征与口面裂建立了这些菌株作为进一步解剖这种先天性颅面畸形复杂性的独特工具。本研究将PBX TALE同源结构域蛋白与上颌形状和大小的变化密切联系起来，这种变化发生在病理环境和中面部形态的进化过程中。
Orofacial clefting represents the most common craniofacial birth defect. Cleft lip with or without cleft palate (CL/P) is genetically distinct from cleft palate only (CPO). Numerous transcription factors (TFs) regulate normal development of the midface, comprising the premaxilla, maxilla and palatine bones, through control of basic cellular behaviors. Within the Pbx family of genes encoding Three Amino‐acid Loop Extension (TALE) homeodomain‐containing TFs, we previously established that in the mouse, Pbx1 plays a preeminent role in midfacial morphogenesis, and Pbx2 and Pbx3 execute collaborative functions in domains of coexpression. We also reported that Pbx1 loss from cephalic epithelial domains, on a Pbx2‐ or Pbx3‐deficient background, results in CL/P via disruption of a regulatory network that controls apoptosis at the seam of frontonasal and maxillary process fusion. Conversely, Pbx1 loss in cranial neural crest cell (CNCC)‐derived mesenchyme on a Pbx2‐deficient background results in CPO, a phenotype not yet characterized. In this study, we provide in‐depth analysis of PBX1 and PBX2 protein localization from early stages of midfacial morphogenesis throughout development of the secondary palate. We further establish CNCC‐specific roles of PBX TFs and describe the developmental abnormalities resulting from their loss in the murine embryonic secondary palate. Additionally, we compare and contrast the phenotypes arising from PBX1 loss in CNCC with those caused by its loss in the epithelium and show that CNCC‐specific Pbx1 deletion affects only later secondary palate morphogenesis. Moreover, CNCC mutants exhibit perturbed rostro‐caudal organization and broadening of the midfacial complex. Proliferation defects are pronounced in CNCC mutants at gestational day (E)12.5, suggesting altered proliferation of mutant palatal progenitor cells, consistent with roles of PBX factors in maintaining progenitor cell state. Although the craniofacial skeletal abnormalities in CNCC mutants do not result from overt patterning defects, osteogenesis is delayed, underscoring a critical role of PBX factors in CNCC morphogenesis and differentiation. Overall, the characterization of tissue‐specific Pbx loss‐of‐function mouse models with orofacial clefting establishes these strains as unique tools to further dissect the complexities of this congenital craniofacial malformation. This study closely links PBX TALE homeodomain proteins to the variation in maxillary shape and size that occurs in pathological settings and during evolution of midfacial morphology.
登录
查看更多内容
影响因子：
2.4
作者：
de la Cuadra-Blanco, C;Peces-Peña, MD;Mérida-Velasco, JR
通讯作者：
Mérida-Velasco, JR
影响因子：
4.6
作者：
Capellini, Terence D.;Vaccari, Giulia;Zappavigna, Vincenzo
通讯作者：
Zappavigna, Vincenzo
影响因子：
3.5
作者：
Clement-Jones, M;Schiller, S;Rappold, GA
通讯作者：
Rappold, GA
影响因子：
2.5
作者：
Capellini, Terence D.;Zappavigna, Vincenzo;Selleri, Licia
通讯作者：
Selleri, Licia
DOI：
10.1073/pnas.95.5.2406
发表时间：
1998-03-03
影响因子：
11.1
作者：
Blaschke, RJ;Monaghan, AP;Rappold, GA
通讯作者：
Rappold, GA