Multiple tissue-specific requirements for the BMP antagonist Noggin in development of the mammalian craniofacial skeleton.
Multiple tissue-specific requirements for the BMP antagonist Noggin in development of the mammalian craniofacial skeleton.
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DOI：
10.1016/j.ydbio.2014.06.006
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发表时间：
2014-08-15
影响因子：
2.7
通讯作者：
Klingensmith, John
中科院分区：
文献类型：
--
作者：
Matsui, Maiko;Klingensmith, John
哺乳动物的头面部骨骼由二十多个小软骨和骨骼组成，正确的形态发生对其形态和功能都是必不可少的。支撑口腔的骨骼元素来自于发育在咽弓1(PA1)的上颌芽和下颌芽中的颅神经脊细胞(NCC)。骨形态发生蛋白(BMP)信号转导与颅面骨形成的许多方面有关，包括PA1的发育。然而，BMP拮抗剂Noggin在头面部骨骼形成中的作用尚不清楚，部分原因是它在形成阶段有多个表达区域。在这里，我们使用组织特异性基因消融的方法来评估Noggin(Nog)在两个可能与下颌和上颌发育相关的不同组织区域中的作用。我们发现，NOG的轴向中线结构域在早期促进PA1的发育是至关重要的，这是下颌芽充分生长所必需的。随后，Nog在NCCs中的表达调节头面部软骨和骨的形成。NCC中缺乏NOG的小鼠下颌骨变大，这是由于Meckel‘s软骨内和周围细胞增殖增加所致。这些突变体还表现出完全性继发性腭裂，很可能是由于发育中的颅底形态破坏而抑制了后腭架的抬高。我们的发现证明了Noggin在不同的颅面骨骼形成领域中的多种作用，并提示了Nog突变导致继发性腭裂的间接机制，这可能也与人类腭裂有关。
Proper morphogenesis is essential for both form and function of the mammalian craniofacial skeleton, which consists of more than twenty small cartilages and bones. Skeletal elements that support the oral cavity are derived from cranial neural crest cells (NCCs) that develop in the maxillary and mandibular buds of pharyngeal arch 1 (PA1). Bone Morphogenetic Protein (BMP) signaling has been implicated in most aspects of craniofacial skeletogenesis, including PA1 development. However, the roles of the BMP antagonist Noggin in formation of the craniofacial skeleton remain unclear, in part because of its multiple domains of expression during formative stages. Here we used a tissue-specific gene ablation approach to assess roles of Noggin (Nog) in two different tissue domains potentially relevant to mandibular and maxillary development. We found that the axial midline domain of Nog expression is critical to promote PA1 development in early stages, necessary for adequate outgrowth of the mandibular bud. Subsequently, Nog expression in NCCs regulates craniofacial cartilage and bone formation. Mice lacking Nog in NCCs have an enlarged mandible that results from increased cell proliferation in and around Meckel’s cartilage. These mutants also show complete secondary cleft palate, most likely due to inhibition of posterior palatal shelf elevation by disrupted morphology of the developing skull base. Our findings demonstrate multiple roles of Noggin in different domains for craniofacial skeletogenesis, and suggest an indirect mechanism for secondary cleft palate in Nog mutants that may be relevant to human cleft palate as well.
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