Augmented BMP signaling commits cranial neural crest cells to a chondrogenic fate by suppressing autophagic β-catenin degradation.
Augmented BMP signaling commits cranial neural crest cells to a chondrogenic fate by suppressing autophagic β-catenin degradation.
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DOI：
10.1126/scisignal.aaz9368
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发表时间：
2021-01-12
影响因子：
7.3
通讯作者：
Mishina Y
中科院分区：
文献类型：
--
作者：
Yang J;Kitami M;Pan H;Nakamura MT;Zhang H;Liu F;Zhu L;Komatsu Y;Mishina Y
颅神经嵴细胞（cncc）是一个多能干细胞群体，在发育过程中产生颅面骨和软骨。骨形态发生蛋白（BMP）信号传导和自噬分别与干细胞稳态有关。导致BMP I型受体ACVR1组成性激活的突变导致进行性骨化纤维发育不良（FOP）的先天性疾病，其特征是躯干结缔组织的软骨和骨异位，有时包括颅面骨异位。本研究表明，通过自噬依赖机制，增强BMP信号通过小鼠cncc中组成性激活的ACVR1 （ca-ACVR1）诱导颅面区异位软骨形成。增强的BMP信号通过激活mTORC1抑制自噬，从而阻断β-catenin的自噬降解，进而导致cncc采用软骨细胞身份。短暂阻断mTORC1、自噬再激活或抑制Wnt -β-catenin信号传导可减少ca-Acvr1突变体的异位软骨。我们的研究结果表明，BMP信号和自噬协调调节β-catenin活性，以指导颅面发育过程中cncc的命运。这些发现也可以解释为什么一些FOP患者通过颅面区域的软骨内成骨而发生异位骨。
Cranial neural crest cells (CNCCs) are a population of multipotent stem cells that give rise to craniofacial bone and cartilage during development. Bone morphogenetic protein (BMP) signaling and autophagy have been individually implicated in stem cell homeostasis. Mutations that cause constitutive activation of the BMP type I receptor ACVR1 cause the congenital disorder fibrodysplasia ossificans progressiva (FOP), which is characterized by ectopic cartilage and bone in connective tissues in the trunk and sometimes includes ectopic craniofacial bones. Here, we showed that enhanced BMP signaling through the constitutively activated ACVR1 (ca-ACVR1) in CNCCs in mice induced ectopic cartilage formation in the craniofacial region through an autophagy-dependent mechanism. Enhanced BMP signaling suppressed autophagy by activating mTORC1, thus blocking the autophagic degradation of β-catenin, which, in turn, caused CNCCs to adopt a chondrogenic identity. Transient blockade of mTORC1, reactivation of autophagy, or suppression of Wnt–β-catenin signaling reduced ectopic cartilages in ca-Acvr1 mutants. Our results suggest that BMP signaling and autophagy coordinately regulate β-catenin activity to direct the fate of CNCCs during craniofacial development. These findings may also explain why some patients with FOP develop ectopic bones through endochondral ossification in craniofacial regions.
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影响因子：
5.2
作者：
Chung, Il-Hyuk;Yamaza, Takayoshi;Zhao, Hu;Choung, Pill-Hoon;Shi, Songtao;Chai, Yang
通讯作者：
Chai, Yang
DOI：
10.1016/j.tripleo.2010.12.002
发表时间：
2011-04-01
期刊：
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY AND ENDODONTOLOGY
影响因子：
--
作者：
Carvalho, Daniel Rocha;Farage, Luciano;Speck-Martins, Carlos Eduardo
通讯作者：
Speck-Martins, Carlos Eduardo
影响因子：
7.2
作者：
Grafe I;Alexander S;Peterson JR;Snider TN;Levi B;Lee B;Mishina Y
通讯作者：
Mishina Y
DOI：
10.1073/pnas.85.14.5325
发表时间：
1988-07-01
影响因子：
11.1
作者：
BAROFFIO, A;DUPIN, E;LEDOUARIN, NM
通讯作者：
LEDOUARIN, NM
影响因子：
11.8
作者：
Day, TF;Guo, XZ;Yang, YZ
通讯作者：
Yang, YZ