Warren Stephen M, Brunet Lisa J, Harland Richard M, Economides Aris N, Longaker Michael T
Department of Surgery, Stanford University School of Medicine, Stanford, California 94305-5148, USA.
Nature. 2003 Apr 10;422(6932):625-9. doi: 10.1038/nature01545.
During skull development, the cranial connective tissue framework undergoes intramembranous ossification to form skull bones (calvaria). As the calvarial bones advance to envelop the brain, fibrous sutures form between the calvarial plates. Expansion of the brain is coupled with calvarial growth through a series of tissue interactions within the cranial suture complex. Craniosynostosis, or premature cranial suture fusion, results in an abnormal skull shape, blindness and mental retardation. Recent studies have demonstrated that gain-of-function mutations in fibroblast growth factor receptors (fgfr) are associated with syndromic forms of craniosynostosis. Noggin, an antagonist of bone morphogenetic proteins (BMPs), is required for embryonic neural tube, somites and skeleton patterning. Here we show that noggin is expressed postnatally in the suture mesenchyme of patent, but not fusing, cranial sutures, and that noggin expression is suppressed by FGF2 and syndromic fgfr signalling. Since noggin misexpression prevents cranial suture fusion in vitro and in vivo, we suggest that syndromic fgfr-mediated craniosynostoses may be the result of inappropriate downregulation of noggin expression.
在颅骨发育过程中，颅骨结缔组织框架通过膜内成骨形成颅骨（颅盖）。随着颅盖骨向前包绕大脑，颅盖骨板之间形成纤维性缝线。大脑的生长与颅盖骨的生长通过颅缝复合体中的一系列组织相互作用相耦合。颅缝早闭，即颅骨缝线过早融合，会导致颅骨形状异常、失明和智力迟钝。最近的研究表明，成纤维细胞生长因子受体（fgfr）的功能获得性突变与综合征性颅缝早闭有关。骨形态发生蛋白（BMP）的拮抗剂Noggin是胚胎神经管、体节和骨骼模式形成所必需的。在这里，我们表明Noggin在出生后在开放的而非融合的颅骨缝线的间充质中表达，并且Noggin的表达受到FGF2和综合征性fgfr信号的抑制。由于Noggin的错误表达在体外和体内均可阻止颅骨缝线融合，我们认为综合征性fgfr介导的颅缝早闭可能是Noggin表达不适当下调的结果。
