Shox2 regulates osteogenic differentiation and pattern formation during hard palate development in mice
Shox2 regulates osteogenic differentiation and pattern formation during hard palate development in mice
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Shox2在小鼠硬腭发育过程中调节成骨分化和模式形成
DOI：
10.1074/jbc.ra119.008801
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发表时间：
2019-11-29
影响因子：
4.8
通讯作者：
Chen, YiPing
中科院分区：
文献类型：
--
作者：
Xu, Jue;Wang, Linyan;Chen, YiPing
在哺乳动物腭裂发生过程中，颅神经沟来源的间充质细胞经过成骨分化形成硬腭，硬腭分为上颌骨的腭突和腭突。然而，目前尚不清楚这些骨质结构是否起源于相同的细胞谱系，以及硬腭是如何在分子水平上形成图案的。在小鼠身上，我们报告了Shox2(Short Stature Homeobox 2)的缺陷，Shox2(Short Stature Homeobox 2)是一种转录调节因子，其表达仅限于前腭间充质，导致上颌骨的腭突缺陷，但不影响腭骨。Shox2在腭间充质中的过度表达导致上颌骨的腭突增生和腭突发育不良。RNA测序和转座酶可及染色质测序分析表明，Shox2控制着与前腭部可及染色质相关的模式规范和骨骼生成基因的表达。这突出了Shox2在硬腭的图案化和成骨中的谱系自主功能。H3K27ac芯片序列和瞬时转基因增强子分析表明，Shox2以前腭部特异的方式与远端作用的顺式调节元件结合。我们的结果表明，上颌骨和腭骨的腭突起源于不同的细胞谱系，并具有不同的成骨机制。Shox2通过与远端顺式调控元件相互作用调节成骨基因表达和形成硬腭，明显控制细胞系的成骨，并参与上颌骨的腭突。全基因组Shox2基因在腭部发育中的占有率可能为鉴定活跃的前腭部特异性基因增强子提供一个标记物。
During mammalian palatogenesis, cranial neural crest-derived mesenchymal cells undergo osteogenic differentiation and form the hard palate, which is divided into palatine process of the maxilla and the palatine. However, it remains unknown whether these bony structures originate from the same cell lineage and how the hard palate is patterned at the molecular level. Using mice, here we report that deficiency in Shox2 (short stature homeobox 2), a transcriptional regulator whose expression is restricted to the anterior palatal mesenchyme, leads to a defective palatine process of the maxilla but does not affect the palatine. Shox2 overexpression in palatal mesenchyme resulted in a hyperplastic palatine process of the maxilla and a hypoplastic palatine. RNA sequencing and assay for transposase-accessible chromatin-sequencing analyses revealed that Shox2 controls the expression of pattern specification and skeletogenic genes associated with accessible chromatin in the anterior palate. This highlighted a lineage-autonomous function of Shox2 in patterning and osteogenesis of the hard palate. H3K27ac ChIP-Seq and transient transgenic enhancer assays revealed that Shox2 binds distal-acting cis-regulatory elements in an anterior palate–specific manner. Our results suggest that the palatine process of the maxilla and palatine arise from different cell lineages and differ in ossification mechanisms. Shox2 evidently controls osteogenesis of a cell lineage and contributes to the palatine process of the maxilla by interacting with distal cis-regulatory elements to regulate skeletogenic gene expression and to pattern the hard palate. Genome-wide Shox2 occupancy in the developing palate may provide a marker for identifying active anterior palate–specific gene enhancers.