Augmented BMP signaling commits cranial neural crest cells to a chondrogenic fate by suppressing autophagic β-catenin degradation
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 a...
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| Veröffentlicht in: | Science signaling 2021-01, Vol.14 (665) |
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| creator | Yang, Jingwen Kitami, Megumi Pan, Haichun Nakamura, Masako Toda Zhang, Honghao Liu, Fei Zhu, Lingxin Komatsu, Yoshihiro Mishina, Yuji |
| description | 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
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. |
| doi_str_mv | 10.1126/scisignal.aaz9368 |
| format | Article |
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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.</description><identifier>ISSN: 1945-0877</identifier><identifier>EISSN: 1937-9145</identifier><identifier>DOI: 10.1126/scisignal.aaz9368</identifier><identifier>PMID: 33436499</identifier><language>eng</language><publisher>United States: The American Association for the Advancement of Science</publisher><subject>Abnormalities ; Autophagy ; Bone morphogenetic proteins ; Bones ; Cartilage ; Cell fate ; Cell signaling ; Chondrogenesis ; Congenital anomalies ; Connective tissue ; Connective tissue diseases ; Connective tissues ; Craniofacial growth ; Degradation ; Endochondral bone ; Homeostasis ; Mutation ; Myositis ossificans ; Neural crest ; Ossification (ectopic) ; Phagocytosis ; Proteins ; Receptors ; Signaling ; Skull ; Stem cell transplantation ; Stem cells ; Wnt protein ; β-Catenin</subject><ispartof>Science signaling, 2021-01, Vol.14 (665)</ispartof><rights>Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.</rights><rights>Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c427t-e5cc67d2c6cc06cf8fb4a3e99c069a2d760ad2c9d48575c944d7af4e322bc8b43</citedby><cites>FETCH-LOGICAL-c427t-e5cc67d2c6cc06cf8fb4a3e99c069a2d760ad2c9d48575c944d7af4e322bc8b43</cites><orcidid>0000-0002-1588-5388 ; 0000-0002-2646-3009 ; 0000-0001-8969-6486 ; 0000-0002-2338-6992 ; 0000-0002-6762-7882</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,778,782,883,2873,2874,27911,27912</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33436499$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yang, Jingwen</creatorcontrib><creatorcontrib>Kitami, Megumi</creatorcontrib><creatorcontrib>Pan, Haichun</creatorcontrib><creatorcontrib>Nakamura, Masako Toda</creatorcontrib><creatorcontrib>Zhang, Honghao</creatorcontrib><creatorcontrib>Liu, Fei</creatorcontrib><creatorcontrib>Zhu, Lingxin</creatorcontrib><creatorcontrib>Komatsu, Yoshihiro</creatorcontrib><creatorcontrib>Mishina, Yuji</creatorcontrib><title>Augmented BMP signaling commits cranial neural crest cells to a chondrogenic fate by suppressing autophagic β-catenin degradation</title><title>Science signaling</title><addtitle>Sci Signal</addtitle><description>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
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.</description><subject>Abnormalities</subject><subject>Autophagy</subject><subject>Bone morphogenetic proteins</subject><subject>Bones</subject><subject>Cartilage</subject><subject>Cell fate</subject><subject>Cell signaling</subject><subject>Chondrogenesis</subject><subject>Congenital anomalies</subject><subject>Connective tissue</subject><subject>Connective tissue diseases</subject><subject>Connective tissues</subject><subject>Craniofacial growth</subject><subject>Degradation</subject><subject>Endochondral bone</subject><subject>Homeostasis</subject><subject>Mutation</subject><subject>Myositis ossificans</subject><subject>Neural crest</subject><subject>Ossification (ectopic)</subject><subject>Phagocytosis</subject><subject>Proteins</subject><subject>Receptors</subject><subject>Signaling</subject><subject>Skull</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>Wnt protein</subject><subject>β-Catenin</subject><issn>1945-0877</issn><issn>1937-9145</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNpdUctu1TAUjBCIlsIHsEGW2LBJSWzHjjdIpeIlFcEC1tbJsZPrKrGDnSCVJZ_UD-k34XAvV8Dq2Jo5ozMzRfG0rs7rmoqXCV1yg4fxHOCHYqK9V5zWislS1by5v715U1atlCfFo5Suq0rUlKqHxQljnAmu1Gnx82IdJusXa8jrj5_JXs75gWCYJrckghG8g5F4u8Y8MNq0ELTjmMgSCBDcBW9iGKx3SHpYLOluSFrnORPTJgTrEuYdDBm-uy0xM7zzxNghgoHFBf-4eNDDmOyTwzwrvr598-XyfXn16d2Hy4urEjmVS2kbRCENRYFYCezbvuPArFL5p4AaKSrIqDK8bWSDinMjoeeWUdph23F2Vrza685rN1mD2XV2pOfoJog3OoDT_yLe7fQQvmuZo-WizQIvDgIxfFtzDnpyaYsCvA1r0pRL2VS0rZtMff4f9TqsMUf7m9VWiiu-CdZ7FsaQUrT98Zi60lvD-tiwPjScd5797eK48adS9gt-VapY</recordid><startdate>20210112</startdate><enddate>20210112</enddate><creator>Yang, Jingwen</creator><creator>Kitami, Megumi</creator><creator>Pan, Haichun</creator><creator>Nakamura, Masako Toda</creator><creator>Zhang, Honghao</creator><creator>Liu, Fei</creator><creator>Zhu, Lingxin</creator><creator>Komatsu, Yoshihiro</creator><creator>Mishina, Yuji</creator><general>The American Association for the Advancement of Science</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QP</scope><scope>7TK</scope><scope>7TM</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>JQ2</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-1588-5388</orcidid><orcidid>https://orcid.org/0000-0002-2646-3009</orcidid><orcidid>https://orcid.org/0000-0001-8969-6486</orcidid><orcidid>https://orcid.org/0000-0002-2338-6992</orcidid><orcidid>https://orcid.org/0000-0002-6762-7882</orcidid></search><sort><creationdate>20210112</creationdate><title>Augmented BMP signaling commits cranial neural crest cells to a chondrogenic fate by suppressing autophagic β-catenin degradation</title><author>Yang, Jingwen ; Kitami, Megumi ; Pan, Haichun ; Nakamura, Masako Toda ; Zhang, Honghao ; Liu, Fei ; Zhu, Lingxin ; Komatsu, Yoshihiro ; Mishina, Yuji</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c427t-e5cc67d2c6cc06cf8fb4a3e99c069a2d760ad2c9d48575c944d7af4e322bc8b43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Abnormalities</topic><topic>Autophagy</topic><topic>Bone morphogenetic proteins</topic><topic>Bones</topic><topic>Cartilage</topic><topic>Cell fate</topic><topic>Cell signaling</topic><topic>Chondrogenesis</topic><topic>Congenital anomalies</topic><topic>Connective tissue</topic><topic>Connective tissue diseases</topic><topic>Connective tissues</topic><topic>Craniofacial growth</topic><topic>Degradation</topic><topic>Endochondral bone</topic><topic>Homeostasis</topic><topic>Mutation</topic><topic>Myositis ossificans</topic><topic>Neural crest</topic><topic>Ossification (ectopic)</topic><topic>Phagocytosis</topic><topic>Proteins</topic><topic>Receptors</topic><topic>Signaling</topic><topic>Skull</topic><topic>Stem cell transplantation</topic><topic>Stem cells</topic><topic>Wnt protein</topic><topic>β-Catenin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yang, Jingwen</creatorcontrib><creatorcontrib>Kitami, Megumi</creatorcontrib><creatorcontrib>Pan, Haichun</creatorcontrib><creatorcontrib>Nakamura, Masako Toda</creatorcontrib><creatorcontrib>Zhang, Honghao</creatorcontrib><creatorcontrib>Liu, Fei</creatorcontrib><creatorcontrib>Zhu, Lingxin</creatorcontrib><creatorcontrib>Komatsu, Yoshihiro</creatorcontrib><creatorcontrib>Mishina, Yuji</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>ProQuest Computer Science Collection</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Science signaling</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yang, Jingwen</au><au>Kitami, Megumi</au><au>Pan, Haichun</au><au>Nakamura, Masako Toda</au><au>Zhang, Honghao</au><au>Liu, Fei</au><au>Zhu, Lingxin</au><au>Komatsu, Yoshihiro</au><au>Mishina, Yuji</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Augmented BMP signaling commits cranial neural crest cells to a chondrogenic fate by suppressing autophagic β-catenin degradation</atitle><jtitle>Science signaling</jtitle><addtitle>Sci Signal</addtitle><date>2021-01-12</date><risdate>2021</risdate><volume>14</volume><issue>665</issue><issn>1945-0877</issn><eissn>1937-9145</eissn><abstract>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
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.</abstract><cop>United States</cop><pub>The American Association for the Advancement of Science</pub><pmid>33436499</pmid><doi>10.1126/scisignal.aaz9368</doi><orcidid>https://orcid.org/0000-0002-1588-5388</orcidid><orcidid>https://orcid.org/0000-0002-2646-3009</orcidid><orcidid>https://orcid.org/0000-0001-8969-6486</orcidid><orcidid>https://orcid.org/0000-0002-2338-6992</orcidid><orcidid>https://orcid.org/0000-0002-6762-7882</orcidid><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1945-0877 |
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| subjects | Abnormalities Autophagy Bone morphogenetic proteins Bones Cartilage Cell fate Cell signaling Chondrogenesis Congenital anomalies Connective tissue Connective tissue diseases Connective tissues Craniofacial growth Degradation Endochondral bone Homeostasis Mutation Myositis ossificans Neural crest Ossification (ectopic) Phagocytosis Proteins Receptors Signaling Skull Stem cell transplantation Stem cells Wnt protein β-Catenin |
| title | Augmented BMP signaling commits cranial neural crest cells to a chondrogenic fate by suppressing autophagic β-catenin degradation |
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