Crucial and Overlapping Roles of Six1 and Six2 in Craniofacial Development
Crucial and Overlapping Roles of Six1 and Six2 in Craniofacial Development
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DOI：
10.1177/0022034519835204
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发表时间：
2019-05-01
影响因子：
7.6
通讯作者：
Jiang, R.
中科院分区：
文献类型：
--
作者：
Liu, Z.;Li, C.;Jiang, R.
SIX 1和SIX 2编码密切相关的转录因子，这些转录因子的破坏与不同的颅面综合征相关，SIX 1的突变与鳃裂综合征3（BOS 3）相关，SIX 2的杂合缺失与额鼻发育不良缺陷相关。Six 1缺陷的小鼠重现了与BOS 3相关的大部分发育缺陷，而Six 2功能缺陷的小鼠没有明显的额鼻缺陷。我们发现，Six 1和Six 2表现出部分重叠的模式在发育中的小鼠胚胎额鼻，上颌和下颌突的表达。我们发现Six 1（-/-）Six 2（-/-）双突变小鼠出生时具有Six 1（-/-）或Six 2（-/-）单突变小鼠所没有的严重颅面畸形，包括颅骨发育不全、中线面裂和合缝。此外，Six 1（-/-）小鼠表现出部分上颌骨颌骨骨向下颌髁状突样结构的转化，Six 1（-/-）Six 2（+/-）小鼠表现出上颌骨畸形的显著增加。除了最近在E10.5 Six 1（-/-）胚胎中报道的上颌骨-下颌骨连接处的异位Dlx 5表达外，E10.5 Six 1（-/-）Six 2（+/-）胚胎在上颌骨-下颌骨连接处显示出Bmp 4、Msx 1和Msx 2信使RNA的异位表达。在Six 1（-/-）和Six 1（-/-）Six 2（+/-）胚胎中，Ednra或Bmp 4的1个等位基因的遗传失活显著降低了上颌骨畸形的发生率，表明Six 1和Six 2调节内皮素和骨形态发生蛋白-4信号通路以形成面部结构。此外，我们发现Six 2（-/-）胚胎中Six 1的神经嵴特异性失活导致中线面裂和额骨发育不全。我们发现Six 1（-/-）Six 2（-/-）胚胎表现出显着降低的表达额鼻发育的关键基因Alx 1和Alx 3，以及在发展额鼻间充质细胞凋亡增加。总之，这些结果表明，Six 1和Six 2功能部分冗余控制多颅面发育过程中发挥重要的神经嵴细胞自主的作用，在额鼻形态发生。
SIX1 and SIX2 encode closely related transcription factors of which disruptions have been associated with distinct craniofacial syndromes, with mutations in SIX1 associated with branchiootic syndrome 3 (BOS3) and heterozygous deletions of SIX2 associated with frontonasal dysplasia defects. Whereas mice deficient in Six1 recapitulated most of the developmental defects associated with BOS3, mice lacking Six2 function had no obvious frontonasal defects. We show that Six1 and Six2 exhibit partly overlapping patterns of expression in the developing mouse embryonic frontonasal, maxillary, and mandibular processes. We found that Six1(-/-)Six2(-/-) double-mutant mice were born with severe craniofacial deformity not seen in the Six1(-/-) or Six2(-/-) single mutants, including skull bone agenesis, midline facial cleft, and syngnathia. Moreover, whereas Six1(-/-) mice exhibited partial transformation of maxillary zygomatic bone into a mandibular condyle-like structure, Six1(-/-)Six2(+/-) mice exhibit significantly increased penetrance of the maxillary malformation. In addition to ectopic Dlx5 expression at the maxillary-mandibular junction as recently reported in E10.5 Six1(-/-) embryos, the E10.5 Six1(-/-)Six2(+/-) embryos showed ectopic expression of Bmp4, Msx1, and Msx2 messenger RNAs in the maxillary-mandibular junction. Genetically inactivating 1 allele of either Ednra or Bmp4 significantly reduced the penetrance of maxillary malformation in both Six1(-/-) and Six1(-/-)Six2(+/-) embryos, indicating that Six1 and Six2 regulate both endothelin and bone morphogenetic protein-4 signaling pathways to pattern the facial structures. Furthermore, we show that neural crest-specific inactivation of Six1 in Six2(-/-) embryos resulted in midline facial cleft and frontal bone agenesis. We show that Six1(-/-)Six2(-/-) embryos exhibit significantly reduced expression of key frontonasal development genes Alx1 and Alx3 as well as increased apoptosis in the developing frontonasal mesenchyme. Together, these results indicate that Six1 and Six2 function partly redundantly to control multiple craniofacial developmental processes and play a crucial neural crest cell-autonomous role in frontonasal morphogenesis.