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Lhx6 deficiency causes human embryonic palatal mesenchymal cell mitophagy dysfunction in cleft palate

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Title: Lhx6 deficiency causes human embryonic palatal mesenchymal cell mitophagy dysfunction in cleft palate
Authors: Haotian Luo, Hio Cheng Ieong, Runze Li, Delan Huang, Danying Chen, Xin Chen, Yuqing Guo, Yangqiao Qing, Bingyan Guo, Ruoyu Li, Yungshan Teng, Wenfeng Li, Yang Cao, Chen Zhou, Weicai Wang
Source: Molecular Medicine, Vol 30, Iss 1, Pp 1-18 (2024)
Publisher Information: BMC, 2024.
Publication Year: 2024
Collection: LCC:Therapeutics. Pharmacology
LCC:Biochemistry
Subject Terms: Cleft palate, Retinoic acid, Embryonic palatal mesenchymal cells, Lhx6, PINK1, Mitophagy, Therapeutics. Pharmacology, RM1-950, Biochemistry, QD415-436
More Details: Abstract Background Overconsumption of retinoic acid (RA) or its analogues/derivatives has been linked to severe craniomaxillofacial malformations, such as cleft palate and midface hypoplasia. It has been noted that RA disturbed the proliferation and migration of embryonic palatal mesenchymal (EPM) cells in these malformations, yet the exact mechanisms underlying these disruptions remained unclear. Methods A model of retinoic acid (RA)-induced cleft palate in fetal mice was successfully established. Histological alterations in the palate were evaluated using Hematoxylin and Eosin (H&E) staining and RNA in situ hybridization (RNAscope). Cellular proliferation levels were quantified via the Cell Counting Kit-8 (CCK-8) assay and EdU incorporation assay, while cell migration capabilities were investigated using wound healing and Transwell assays. Mitochondrial functions were assessed through Mito-Tracker fluorescence, mitochondrial reactive oxygen species (ROS) measurement, ATP level quantification, and mitochondrial DNA (mtDNA) copy number analysis. Differential gene expression and associated signaling pathways were identified through bioinformatics analysis. Alterations in the transcriptional and translational levels of Lhx6 and genes associated with mitophagy were quantified using quantitative PCR (qPCR) and Western blot analysis, respectively. Mitochondrial morphology and the mitochondrial autophagosomes within cells were examined through transmission electron microscopy (TEM). Results Abnormal palatal development in mice, along with impaired proliferation and migration of human embryonic palatal mesenchymal (HEPM) cells, was associated with RA affecting mitochondrial function and concomitant downregulation of Lhx6. Knockdown of Lhx6 in HEPM cells resulted in altered cell proliferation, migration, and mitochondrial function. Conversely, the aberrant mitochondrial function, proliferation, and migration observed in RA-induced HEPM cells were ameliorated by overexpression of Lhx6. Subsequent research demonstrated that Lhx6 ameliorated RA-induced dysfunction in HEPM cells by modulating PINK1/Parkin-mediated mitophagy, thereby activating the MAPK signaling pathways. Conclusion Lhx6 is essential for mitochondrial homeostasis via tuning PINK1/Parkin-mediated mitophagy and MAPK signaling pathways. Downregulation of Lhx6 by RA transcriptionally disturbs the mitochondrial homeostasis, which in turn leads to the proliferation and migration defect in HEPM cells, ultimately causing the cleft palate. Graphical abstract
Document Type: article
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Language: English
ISSN: 1528-3658
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DOI: 10.1186/s10020-024-00960-2
Access URL: https://doaj.org/article/56a007c8bd9340c7a52809ed7bef7201
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  Data: Lhx6 deficiency causes human embryonic palatal mesenchymal cell mitophagy dysfunction in cleft palate
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  Data: <searchLink fieldCode="AR" term="%22Haotian+Luo%22">Haotian Luo</searchLink><br /><searchLink fieldCode="AR" term="%22Hio+Cheng+Ieong%22">Hio Cheng Ieong</searchLink><br /><searchLink fieldCode="AR" term="%22Runze+Li%22">Runze Li</searchLink><br /><searchLink fieldCode="AR" term="%22Delan+Huang%22">Delan Huang</searchLink><br /><searchLink fieldCode="AR" term="%22Danying+Chen%22">Danying Chen</searchLink><br /><searchLink fieldCode="AR" term="%22Xin+Chen%22">Xin Chen</searchLink><br /><searchLink fieldCode="AR" term="%22Yuqing+Guo%22">Yuqing Guo</searchLink><br /><searchLink fieldCode="AR" term="%22Yangqiao+Qing%22">Yangqiao Qing</searchLink><br /><searchLink fieldCode="AR" term="%22Bingyan+Guo%22">Bingyan Guo</searchLink><br /><searchLink fieldCode="AR" term="%22Ruoyu+Li%22">Ruoyu Li</searchLink><br /><searchLink fieldCode="AR" term="%22Yungshan+Teng%22">Yungshan Teng</searchLink><br /><searchLink fieldCode="AR" term="%22Wenfeng+Li%22">Wenfeng Li</searchLink><br /><searchLink fieldCode="AR" term="%22Yang+Cao%22">Yang Cao</searchLink><br /><searchLink fieldCode="AR" term="%22Chen+Zhou%22">Chen Zhou</searchLink><br /><searchLink fieldCode="AR" term="%22Weicai+Wang%22">Weicai Wang</searchLink>
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  Data: Molecular Medicine, Vol 30, Iss 1, Pp 1-18 (2024)
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  Data: LCC:Therapeutics. Pharmacology<br />LCC:Biochemistry
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  Data: <searchLink fieldCode="DE" term="%22Cleft+palate%22">Cleft palate</searchLink><br /><searchLink fieldCode="DE" term="%22Retinoic+acid%22">Retinoic acid</searchLink><br /><searchLink fieldCode="DE" term="%22Embryonic+palatal+mesenchymal+cells%22">Embryonic palatal mesenchymal cells</searchLink><br /><searchLink fieldCode="DE" term="%22Lhx6%22">Lhx6</searchLink><br /><searchLink fieldCode="DE" term="%22PINK1%22">PINK1</searchLink><br /><searchLink fieldCode="DE" term="%22Mitophagy%22">Mitophagy</searchLink><br /><searchLink fieldCode="DE" term="%22Therapeutics%2E+Pharmacology%22">Therapeutics. Pharmacology</searchLink><br /><searchLink fieldCode="DE" term="%22RM1-950%22">RM1-950</searchLink><br /><searchLink fieldCode="DE" term="%22Biochemistry%22">Biochemistry</searchLink><br /><searchLink fieldCode="DE" term="%22QD415-436%22">QD415-436</searchLink>
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  Label: Description
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  Data: Abstract Background Overconsumption of retinoic acid (RA) or its analogues/derivatives has been linked to severe craniomaxillofacial malformations, such as cleft palate and midface hypoplasia. It has been noted that RA disturbed the proliferation and migration of embryonic palatal mesenchymal (EPM) cells in these malformations, yet the exact mechanisms underlying these disruptions remained unclear. Methods A model of retinoic acid (RA)-induced cleft palate in fetal mice was successfully established. Histological alterations in the palate were evaluated using Hematoxylin and Eosin (H&E) staining and RNA in situ hybridization (RNAscope). Cellular proliferation levels were quantified via the Cell Counting Kit-8 (CCK-8) assay and EdU incorporation assay, while cell migration capabilities were investigated using wound healing and Transwell assays. Mitochondrial functions were assessed through Mito-Tracker fluorescence, mitochondrial reactive oxygen species (ROS) measurement, ATP level quantification, and mitochondrial DNA (mtDNA) copy number analysis. Differential gene expression and associated signaling pathways were identified through bioinformatics analysis. Alterations in the transcriptional and translational levels of Lhx6 and genes associated with mitophagy were quantified using quantitative PCR (qPCR) and Western blot analysis, respectively. Mitochondrial morphology and the mitochondrial autophagosomes within cells were examined through transmission electron microscopy (TEM). Results Abnormal palatal development in mice, along with impaired proliferation and migration of human embryonic palatal mesenchymal (HEPM) cells, was associated with RA affecting mitochondrial function and concomitant downregulation of Lhx6. Knockdown of Lhx6 in HEPM cells resulted in altered cell proliferation, migration, and mitochondrial function. Conversely, the aberrant mitochondrial function, proliferation, and migration observed in RA-induced HEPM cells were ameliorated by overexpression of Lhx6. Subsequent research demonstrated that Lhx6 ameliorated RA-induced dysfunction in HEPM cells by modulating PINK1/Parkin-mediated mitophagy, thereby activating the MAPK signaling pathways. Conclusion Lhx6 is essential for mitochondrial homeostasis via tuning PINK1/Parkin-mediated mitophagy and MAPK signaling pathways. Downregulation of Lhx6 by RA transcriptionally disturbs the mitochondrial homeostasis, which in turn leads to the proliferation and migration defect in HEPM cells, ultimately causing the cleft palate. Graphical abstract
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      – SubjectFull: Cleft palate
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      – SubjectFull: Retinoic acid
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      – SubjectFull: Embryonic palatal mesenchymal cells
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