Noonan syndrome is associated with enhanced pERK activity, the repression of which can prevent craniofacial malformations
Noonan syndrome is associated with enhanced pERK activity, the repression of which can prevent craniofacial malformations
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DOI：
10.1073/pnas.0903302106
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发表时间：
2009-09-08
影响因子：
11.1
通讯作者：
Robbins, Jeffrey
中科院分区：
文献类型：
--
作者：
Nakamura, Tomoki;Gulick, James;Robbins, Jeffrey
PTPN 11编码的蛋白磷酸酶SHP 2的功能获得突变导致努南综合征（NS），其部分特征在于心脏和颅骨领域的发育缺陷。以前，我们发现突变蛋白SHP 2 Q79 R在心脏中的表达导致了模拟NS某些方面的表型呈现，并且这依赖于ERK 1/2通路的激活。为了理解ERK 1/2信号通过神经嵴中的信号传导在颅骨发育中所起的作用，我们探索了神经嵴细胞中Q79 R表达的后果，神经嵴细胞有助于颅骨的骨和软骨结构的子集。ERK 1/2的过度激活导致颅面缺损，包括颅骨长度变小、内眦距离变大和额骨高度变高。与较小的头骨长度成比例，下颌骨长度也减少了。通过在妊娠期间注射MAPK/ERK激酶抑制剂U 0126来抑制Q79 R表达导致的ERK 1/2过度活性。该药物有效地降低了颅面缺损的严重程度，恢复了正常的颅骨形状和前囟闭合。对头部的X射线计算机辅助显微断层扫描分析证实，降低ERK 1/2活性导致小鼠中出现的颅面缺陷和大脑形状变化消失。这些数据表明，正常的ERK 1/2信号在神经嵴是必要的正常颅面发育，并提供深入了解心脏和颅面发育领域可能会受到影响，在一些先天性综合征介绍。
A gain of function mutation in SHP2, a protein phosphatase encoded by PTPN11, causes Noonan syndrome (NS), which is characterized in part by developmental deficits in both the cardiac and skull fields. Previously, we found that expression of the mutated protein SHP2 Q79R in the heart led to a phenotypic presentation that mimicked some aspects of NS and that this was dependent upon activation of the ERK1/2 pathway. To understand the role that ERK1/2 signaling plays in skull development through signaling in the neural crest, we explored the consequences of Q79R expression in neural crest cells, which contribute to a subset of the bony and cartilaginous structures of the skull. Hyperactivation of ERK1/2 led to craniofacial defects that included smaller skull lengths, greater inner canthal distances, and taller frontal bone heights. In proportion to the smaller skull length, mandibular bone length was also reduced. Inhibition of ERK1/2 hyperactivity as a result of Q79R expression was achieved by injection of the MAPK/ERK kinase inhibitor U0126 during pregnancy. The drug effectively decreased the severity of the craniofacial defects and restored normal skull shape and fontanelle closure. X-ray computer-assisted microtomography analysis of the head confirmed that decreasing ERK1/2 activity led to an abrogation of the craniofacial deficits and brain shape changes that presented in the mice. These data show that normal ERK1/2 signaling in the neural crest is imperative for normal craniofacial development and offer insight into how the heart and craniofacial developmental fields might be affected in some congenital syndromic presentations.