Rap1b Is an Effector of Axin2 Regulating Crosstalk of Signaling Pathways During Skeletal Development.
Rap1b Is an Effector of Axin2 Regulating Crosstalk of Signaling Pathways During Skeletal Development.
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DOI：
10.1002/jbmr.3171
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发表时间：
2017-09
期刊：
影响因子：
--
通讯作者：
Hsu W
中科院分区：
文献类型：
--
作者：
Maruyama T;Jiang M;Abbott A;Yu HI;Huang Q;Chrzanowska-Wodnicka M;Chen EI;Hsu W
最近对能够长期自我更新、克隆扩增和分化的颅缝干细胞的鉴定和分离，证明了它们在颅骨发育、内稳态和损伤修复中的重要作用。这些真正的干细胞高水平表达轴蛋白2（Axin2），并且能够以细胞自主的方式介导骨再生和修复。轴蛋白2的重要性通过在小鼠中其基因失活进一步得到证明，这会导致类似于人类颅缝早闭的骨骼畸形。轴蛋白2阳性干细胞的命运决定和后续分化受到多种进化上保守的信号通路的高度调控，包括Wnt、成纤维细胞生长因子（FGF）和骨形态发生蛋白（BMP）。这些信号通常相互拮抗，并且对成骨细胞和软骨细胞类型具有不同的影响。然而，这些信号转导相互作用的潜在机制在很大程度上仍然不清楚。在这里，我们确定了作为轴蛋白2下游的Rap1b是FGF和BMP的信号调节因子。遗传学分析表明，Rap1b对颅面和身体骨骼的发育至关重要。轴蛋白2通过调节经典的BMP信号来调控Rap1b。BMP介导的Rap1b激活促进软骨形成命运和软骨发生。此外，通过抑制丝裂原活化蛋白激酶（MAPK）信号，Rap1b介导BMP对FGF的拮抗作用以抑制成骨细胞分化。在小鼠中Rap1b的破坏不仅增强成骨细胞分化，而且分别在膜内成骨和软骨内成骨过程中损害软骨细胞分化，导致颅面和身体骨骼的严重缺陷。我们的研究结果揭示了Rap1b在骨骼生成细胞类型发育中的双重作用。Rap1b对于在骨骼发育和疾病过程中平衡BMP和FGF的信号效应至关重要。
Recent identification and isolation of suture stem cells capable of long term self-renewal, clonal expanding and differentiating demonstrate their essential role in calvarial bone development, homeostasis and injury repair. These bona fide stem cells express high level of Axin2 and are able to mediate bone regeneration and repair in a cell autonomous fashion. The importance of Axin2 is further demonstrated by its genetic inactivation in mice causing skeletal deformities resembling craniosynostosis in humans. The fate determination and subsequent differentiation of Axin2+ stem cells are highly orchestrated by a variety of evolutionary conserved signaling pathways including Wnt, FGF and BMP. These signals are often antagonistic of each other and possess differential effects on osteogenic and chondrogenic cell types. However, the mechanisms underlying the interplay of these signaling transductions remain largely elusive. Here we identify Rap1b acting downstream of Axin2 as a signaling interrogator for FGF and BMP. Genetic analysis reveals that Rap1b is essential for development of craniofacial and body skeletons. Axin2 regulates Rap1b through modulation of canonical BMP signaling. The BMP-mediated activation of Rap1b promotes chondrogenic fate and chondrogenesis. Furthermore, by inhibiting MAPK signaling, Rap1b mediates the antagonizing effect of BMP on FGF to repress osteoblast differentiation. Disruption of Rap1b in mice not only enhances osteoblast differentiation but also impairs chondrocyte differentiation during intramembranous and endochondral ossifications, respectively, leading to severe defects in craniofacial and body skeletons. Our findings reveal a dual role of Rap1b in development of the skeletogenic cell types. Rap1b is critical for balancing the signaling effects of BMP and FGF during skeletal development and disease.
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影响因子：
12.4
作者：
通讯作者：
--
DOI：
10.1038/nrm3255
发表时间：
2011-12-22
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
2.1
作者：
Krakow D
通讯作者：
Krakow D
影响因子：
20.3
作者：
Lakshmikanthan, Sribalaji;Sobczak, Magdalena;Chrzanowska-Wodnicka, Magdalena
通讯作者：
Chrzanowska-Wodnicka, Magdalena
影响因子：
3.1
作者：
KREIBORG, S;MARSH, JL;VANNIER, MW
通讯作者：
VANNIER, MW