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Loss of Tctn3 causes neuronal apoptosis and neural tube defects in mice
Tctn3 belongs to the Tectonic (Tctn) family and is a single-pass membrane protein localized at the transition zone of primary cilia as an important component of ciliopathy-related protein complexes. Previous studies showed that mutations in Tctn1 and Tctn2, two members of the tectonic family, have b...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938703/ https://www.ncbi.nlm.nih.gov/pubmed/29725084 http://dx.doi.org/10.1038/s41419-018-0563-4 |
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author | Wang, Bin Zhang, Yingying Dong, Hongli Gong, Siyi Wei, Bin Luo, Man Wang, Hongyan Wu, Xiaohui Liu, Wei Xu, Xingshun Zheng, Yufang Sun, Miao |
author_facet | Wang, Bin Zhang, Yingying Dong, Hongli Gong, Siyi Wei, Bin Luo, Man Wang, Hongyan Wu, Xiaohui Liu, Wei Xu, Xingshun Zheng, Yufang Sun, Miao |
author_sort | Wang, Bin |
collection | PubMed |
description | Tctn3 belongs to the Tectonic (Tctn) family and is a single-pass membrane protein localized at the transition zone of primary cilia as an important component of ciliopathy-related protein complexes. Previous studies showed that mutations in Tctn1 and Tctn2, two members of the tectonic family, have been reported to disrupt neural tube development in humans and mice, but the functions of Tctn3 in brain development remain elusive. In this study, Tctn3 knockout (KO) mice were generated by utilizing the piggyBac (PB) transposon system. We found that Tctn3 KO mice exhibited abnormal global development, including prenatal lethality, microphthalmia, polysyndactyly, and abnormal head, sternum, and neural tube, whereas Tctn3 heterozygous KO mice did not show abnormal development or behaviors. Further, we found that the mRNA levels of Gli1 and Ptch1, downstream signaling components of the Shh pathway, were significantly reduced. Likewise, neural tube patterning-related proteins, such as Shh, Foxa2, and Nkx2.2, were altered in their distribution. Interestingly, Tctn3 KO led to significant changes in apoptosis-related proteins, including Bcl-2, Bax, and cleaved PARP1, resulting in reduced numbers of neuronal cells in embryonic brains. Tctn3 KO inhibited the PI3K/Akt signaling pathway but not the mTOR-dependent pathway. The small molecule SC79, a specific Akt activator, blocked apoptotic cell death in primary mouse embryonic fibroblasts from Tctn3 KO mice. Finally, NPHP1, a protein with anti-apoptotic ability, was found to form a complex with Tctn3, and its levels were decreased in Tctn3 KO mice. In conclusion, our results show that Tctn3 KO disrupts the Shh signaling pathway and neural tube patterning, resulting in abnormal embryonic development, cellular apoptosis, and prenatal death in mice. |
format | Online Article Text |
id | pubmed-5938703 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-59387032018-05-09 Loss of Tctn3 causes neuronal apoptosis and neural tube defects in mice Wang, Bin Zhang, Yingying Dong, Hongli Gong, Siyi Wei, Bin Luo, Man Wang, Hongyan Wu, Xiaohui Liu, Wei Xu, Xingshun Zheng, Yufang Sun, Miao Cell Death Dis Article Tctn3 belongs to the Tectonic (Tctn) family and is a single-pass membrane protein localized at the transition zone of primary cilia as an important component of ciliopathy-related protein complexes. Previous studies showed that mutations in Tctn1 and Tctn2, two members of the tectonic family, have been reported to disrupt neural tube development in humans and mice, but the functions of Tctn3 in brain development remain elusive. In this study, Tctn3 knockout (KO) mice were generated by utilizing the piggyBac (PB) transposon system. We found that Tctn3 KO mice exhibited abnormal global development, including prenatal lethality, microphthalmia, polysyndactyly, and abnormal head, sternum, and neural tube, whereas Tctn3 heterozygous KO mice did not show abnormal development or behaviors. Further, we found that the mRNA levels of Gli1 and Ptch1, downstream signaling components of the Shh pathway, were significantly reduced. Likewise, neural tube patterning-related proteins, such as Shh, Foxa2, and Nkx2.2, were altered in their distribution. Interestingly, Tctn3 KO led to significant changes in apoptosis-related proteins, including Bcl-2, Bax, and cleaved PARP1, resulting in reduced numbers of neuronal cells in embryonic brains. Tctn3 KO inhibited the PI3K/Akt signaling pathway but not the mTOR-dependent pathway. The small molecule SC79, a specific Akt activator, blocked apoptotic cell death in primary mouse embryonic fibroblasts from Tctn3 KO mice. Finally, NPHP1, a protein with anti-apoptotic ability, was found to form a complex with Tctn3, and its levels were decreased in Tctn3 KO mice. In conclusion, our results show that Tctn3 KO disrupts the Shh signaling pathway and neural tube patterning, resulting in abnormal embryonic development, cellular apoptosis, and prenatal death in mice. Nature Publishing Group UK 2018-05-03 /pmc/articles/PMC5938703/ /pubmed/29725084 http://dx.doi.org/10.1038/s41419-018-0563-4 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Wang, Bin Zhang, Yingying Dong, Hongli Gong, Siyi Wei, Bin Luo, Man Wang, Hongyan Wu, Xiaohui Liu, Wei Xu, Xingshun Zheng, Yufang Sun, Miao Loss of Tctn3 causes neuronal apoptosis and neural tube defects in mice |
title | Loss of Tctn3 causes neuronal apoptosis and neural tube defects in mice |
title_full | Loss of Tctn3 causes neuronal apoptosis and neural tube defects in mice |
title_fullStr | Loss of Tctn3 causes neuronal apoptosis and neural tube defects in mice |
title_full_unstemmed | Loss of Tctn3 causes neuronal apoptosis and neural tube defects in mice |
title_short | Loss of Tctn3 causes neuronal apoptosis and neural tube defects in mice |
title_sort | loss of tctn3 causes neuronal apoptosis and neural tube defects in mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938703/ https://www.ncbi.nlm.nih.gov/pubmed/29725084 http://dx.doi.org/10.1038/s41419-018-0563-4 |
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