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Title: Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay

Authors:
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  1. Hungarian Aca. Sci.
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NIHAHAFOREIGNOTHERHHMI
OSTI Identifier:
1241073
Resource Type:
Journal Article
Resource Relation:
Journal Name: eLife; Journal Volume: 5; Journal Issue: 2016
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Kim, Myungjin, Sandford, Erin, Gatica, Damian, Qiu, Yu, Liu, Xu, Zheng, Yumei, Schulman, Brenda A., Xu, Jishu, Semple, Ian, Ro, Seung-Hyun, Kim, Boyoung, Mavioglu, R. Nehir, Tolun, Asl, #305, han,, Jipa, Andras, Takats, Szabolcs, Karpati, Manuela, Li, Jun Z., Yapici, Zuhal, Juhasz, Gabor, Lee, Jun Hee, Klionsky, Daniel J., Burmeister, Margit, SJCH), Michigan), and ITU-Turkey). Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay. United States: N. p., 2016. Web. doi:10.7554/eLife.12245.
Kim, Myungjin, Sandford, Erin, Gatica, Damian, Qiu, Yu, Liu, Xu, Zheng, Yumei, Schulman, Brenda A., Xu, Jishu, Semple, Ian, Ro, Seung-Hyun, Kim, Boyoung, Mavioglu, R. Nehir, Tolun, Asl, #305, han,, Jipa, Andras, Takats, Szabolcs, Karpati, Manuela, Li, Jun Z., Yapici, Zuhal, Juhasz, Gabor, Lee, Jun Hee, Klionsky, Daniel J., Burmeister, Margit, SJCH), Michigan), & ITU-Turkey). Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay. United States. doi:10.7554/eLife.12245.
Kim, Myungjin, Sandford, Erin, Gatica, Damian, Qiu, Yu, Liu, Xu, Zheng, Yumei, Schulman, Brenda A., Xu, Jishu, Semple, Ian, Ro, Seung-Hyun, Kim, Boyoung, Mavioglu, R. Nehir, Tolun, Asl, #305, han,, Jipa, Andras, Takats, Szabolcs, Karpati, Manuela, Li, Jun Z., Yapici, Zuhal, Juhasz, Gabor, Lee, Jun Hee, Klionsky, Daniel J., Burmeister, Margit, SJCH), Michigan), and ITU-Turkey). 2016. "Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay". United States. doi:10.7554/eLife.12245.
@article{osti_1241073,
title = {Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay},
author = {Kim, Myungjin and Sandford, Erin and Gatica, Damian and Qiu, Yu and Liu, Xu and Zheng, Yumei and Schulman, Brenda A. and Xu, Jishu and Semple, Ian and Ro, Seung-Hyun and Kim, Boyoung and Mavioglu, R. Nehir and Tolun, Asl and #305 and han, and Jipa, Andras and Takats, Szabolcs and Karpati, Manuela and Li, Jun Z. and Yapici, Zuhal and Juhasz, Gabor and Lee, Jun Hee and Klionsky, Daniel J. and Burmeister, Margit and SJCH) and Michigan) and ITU-Turkey)},
abstractNote = {},
doi = {10.7554/eLife.12245},
journal = {eLife},
number = 2016,
volume = 5,
place = {United States},
year = 2016,
month = 6
}
  • Highlights: {yields} Deletion of Dicer in vascular smooth muscle cells(VSMCs) leads to embryonic mortality. {yields} Loss of Dicer in VSMCs leads to developmental delay. {yields} Loss of Dicer in VSMCs leads to hemorrhage in various organs including brain, skin and liver. {yields} Loss of Dicer in VSMCs leads to vascular wall remodeling. {yields} Loss of Dicer in VSMCs dysregulates the expression of miRNA and VSMC marker genes. -- Abstract: Dicer is a RNAase III enzyme that cleaves double stranded RNA and generates small interfering RNA (siRNA) and microRNA (miRNA). The goal of this study is to examine the role ofmore » Dicer and miRNAs in vascular smooth muscle cells (VSMCs). We deleted Dicer in VSMCs of mice, which caused a developmental delay that manifested as early as embryonic day E12.5, leading to embryonic death between E14.5 and E15.5 due to extensive hemorrhage in the liver, brain, and skin. Dicer KO embryos showed dilated blood vessels and a disarray of vascular architecture between E14.5 and E15.5. VSMC proliferation was significantly inhibited in Dicer KOs. The expression of VSMC marker genes were significantly downregulated in Dicer cKO embryos. The vascular structure of the yolk sac and embryo in Dicer KOs was lost to an extent that no blood vessels could be identified after E15.5. Expression of most miRNAs examined was compromised in VSMCs of Dicer KO. Our results indicate that Dicer is required for vascular development and regulates vascular remodeling by modulating VSMC proliferation and differentiation.« less
  • Highlights: Black-Right-Pointing-Pointer We generated mice lacking Atg5 and autophagy in keratin K5-positive epithelia. Black-Right-Pointing-Pointer Suppression of autophagy in thymic epithelium was not associated with signs of autoimmunity. Black-Right-Pointing-Pointer Autophagy was required for normal terminal differentiation of preputial gland cells. Black-Right-Pointing-Pointer Autophagy-deficient cells of the preputial glands degraded nuclear DNA prematurely. -- Abstract: Autophagy contributes to the homeostasis of many tissues, yet its role in epithelia is incompletely understood. A recent report proposed that Atg5-dependent autophagy in thymic epithelial cells is essential for their function in the negative selection of self-reactive T-cells and, thus, for the suppression of tissue inflammation. Heremore » we crossed mice carrying floxed alleles of the Atg5 gene with mice expressing the Cre recombinase under the control of the keratin K5 promoter to suppress autophagy in all K5-positive epithelia. The efficiency of autophagy abrogation was confirmed by immunoanalyses of LC3, which was converted to the autophagy-associated LC3-II form in normal but not Atg5-deficient cells, and of p62, which accumulated in Atg5-deficient cells. Mice carrying the epithelium-specific deletion of Atg5 showed normal weight gain, absence of tissue inflammation, and a normal morphology of the thymic epithelium. By contrast, autophagy-deficient epithelial cells of the preputial gland showed aberrant eosinophilic staining in histology and premature degradation of nuclear DNA during terminal differentiation. Taken together, the results of this study suggest that autophagy is dispensable for the suppression of autoimmunity by thymic epithelial cells but essential for normal differentiation of the preputial gland in mice.« less
  • S. cerevisiae Atg5 in complex with the N-terminal regions of Atg16 was expressed, purified and crystallized in four crystal forms. Atg5 is a novel 34 kDa protein that is covalently modified by Atg12, a ubiquitin-like modifier, and forms a complex with Atg16. The Atg12–Atg5–Atg16 complex localizes to autophagosome precursors and plays an essential role in autophagosome formation. Saccharomyces cerevisiae Atg5 in complex with the N-terminal regions of Atg16 was expressed, purified and crystallized in four crystal forms. Forms I, II and III belong to space group P2{sub 1}, with unit-cell parameters a = 66.3, b = 104.4, c = 112.1more » Å, β = 92.1° (form I), a = 79.5, b = 101.4, c = 95.1 Å, β = 98.6° (form II) or a = 56.9, b = 101.2, c = 66.5 Å, β = 100.6° (form III). Form IV belongs to space group P4{sub 2}2{sub 1}2, with unit-cell parameters a = 73.3, c = 148.1 Å. Diffraction data were collected from all crystal forms and high-resolution data to beyond 2.0 Å resolution were obtained from a form IV crystal.« less
  • Highlights: {yields} iPS cells were induced with a fluorescence monitoring system. {yields} ATM-deficient tail-tip fibroblasts exhibited quite a low reprogramming efficiency. {yields} iPS cells obtained from ATM-deficient cells had pluripotent cell characteristics. {yields} ATM-deficient iPS cells had abnormal chromosomes, which were accumulated in culture. -- Abstract: During cell division, one of the major features of somatic cell reprogramming by defined factors, cells are potentially exposed to DNA damage. Inactivation of the tumor suppressor gene p53 raised reprogramming efficiency but resulted in an increased number of abnormal chromosomes in established iPS cells. Ataxia-telangiectasia mutated (ATM), which is critical in the cellularmore » response to DNA double-strand breaks, may also play an important role during reprogramming. To clarify the function of ATM in somatic cell reprogramming, we investigated reprogramming in ATM-deficient (ATM-KO) tail-tip fibroblasts (TTFs). Although reprogramming efficiency was greatly reduced in ATM-KO TTFs, ATM-KO iPS cells were successfully generated and showed the same proliferation activity as WT iPS cells. ATM-KO iPS cells had a gene expression profile similar to ES cells and WT iPS cells, and had the capacity to differentiate into all three germ layers. On the other hand, ATM-KO iPS cells accumulated abnormal genome structures upon continuous passages. Even with the abnormal karyotype, ATM-KO iPS cells retained pluripotent cell characteristics for at least 20 passages. These data indicate that ATM does participate in the reprogramming process, although its role is not essential.« less