Deficiency of the bZIP transcription factors Mafg and Mafk causes misexpression of genes in distinct pathways and results in lens embryonic developmental defects
Deficiency of the small Maf proteins Mafg and Mafk cause multiple defects, namely, progressive neuronal degeneration, cataract, thrombocytopenia and mid-gestational/perinatal lethality. Previous data shows Mafg−/−:Mafk+/- compound knockout (KO) mice exhibit cataracts age 4-months onward. Strikingly,...
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| Format: | Article |
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2022.981893/full |
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| author | Shaili D. Patel Deepti Anand Hozumi Motohashi Fumiki Katsuoka Masayuki Yamamoto Salil A. Lachke Salil A. Lachke |
| author_facet | Shaili D. Patel Deepti Anand Hozumi Motohashi Fumiki Katsuoka Masayuki Yamamoto Salil A. Lachke Salil A. Lachke |
| author_sort | Shaili D. Patel |
| collection | DOAJ |
| description | Deficiency of the small Maf proteins Mafg and Mafk cause multiple defects, namely, progressive neuronal degeneration, cataract, thrombocytopenia and mid-gestational/perinatal lethality. Previous data shows Mafg−/−:Mafk+/- compound knockout (KO) mice exhibit cataracts age 4-months onward. Strikingly, Mafg−/−:Mafk−/− double KO mice develop lens defects significantly early in life, during embryogenesis, but the pathobiology of these defects is unknown, and is addressed here. At embryonic day (E)16.5, the epithelium of lens in Mafg−/−:Mafk−/− animals appears abnormally multilayered as demonstrated by E-cadherin and nuclear staining. Additionally, Mafg−/−:Mafk−/− lenses exhibit abnormal distribution of F-actin near the “fulcrum” region where epithelial cells undergo apical constriction prior to elongation and reorientation as early differentiating fiber cells. To identify the underlying molecular changes, we performed high-throughput RNA-sequencing of E16.5 Mafg−/−:Mafk−/− lenses and identified a cohort of differentially expressed genes that were further prioritized using stringent filtering criteria and validated by RT-qPCR. Several key factors associated with the cytoskeleton, cell cycle or extracellular matrix (e.g., Cdk1, Cdkn1c, Camsap1, Col3a1, Map3k12, Sipa1l1) were mis-expressed in Mafg−/−:Mafk−/− lenses. Further, the congenital cataract-linked extracellular matrix peroxidase Pxdn was significantly overexpressed in Mafg−/−:Mafk−/− lenses, which may cause abnormal cell morphology. These data also identified the ephrin signaling receptor Epha5 to be reduced in Mafg−/−:Mafk−/− lenses. This likely contributes to the Mafg−/−:Mafk−/− multilayered lens epithelium pathology, as loss of an ephrin ligand, Efna5 (ephrin-A5), causes similar lens defects. Together, these findings uncover a novel early function of Mafg and Mafk in lens development and identify their new downstream regulatory relationships with key cellular factors. |
| first_indexed | 2024-04-13T02:11:30Z |
| format | Article |
| id | doaj.art-8dd132b4b3bc435c9b2314fc16bca91d |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-04-13T02:11:30Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-8dd132b4b3bc435c9b2314fc16bca91d2022-12-22T03:07:17ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2022-08-011010.3389/fcell.2022.981893981893Deficiency of the bZIP transcription factors Mafg and Mafk causes misexpression of genes in distinct pathways and results in lens embryonic developmental defectsShaili D. Patel0Deepti Anand1Hozumi Motohashi2Fumiki Katsuoka3Masayuki Yamamoto4Salil A. Lachke5Salil A. Lachke6Department of Biological Sciences, University of Delaware, Newark, DE, United StatesDepartment of Biological Sciences, University of Delaware, Newark, DE, United StatesDepartment of Gene Expression Regulation, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, JapanDepartment of Integrative Genomics, Tohoku University Tohoku Medical Megabank Organization, Sendai, JapanDepartment of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, JapanDepartment of Biological Sciences, University of Delaware, Newark, DE, United StatesCenter for Bioinformatics and Computational Biology, University of Delaware, Newark, DE, United StatesDeficiency of the small Maf proteins Mafg and Mafk cause multiple defects, namely, progressive neuronal degeneration, cataract, thrombocytopenia and mid-gestational/perinatal lethality. Previous data shows Mafg−/−:Mafk+/- compound knockout (KO) mice exhibit cataracts age 4-months onward. Strikingly, Mafg−/−:Mafk−/− double KO mice develop lens defects significantly early in life, during embryogenesis, but the pathobiology of these defects is unknown, and is addressed here. At embryonic day (E)16.5, the epithelium of lens in Mafg−/−:Mafk−/− animals appears abnormally multilayered as demonstrated by E-cadherin and nuclear staining. Additionally, Mafg−/−:Mafk−/− lenses exhibit abnormal distribution of F-actin near the “fulcrum” region where epithelial cells undergo apical constriction prior to elongation and reorientation as early differentiating fiber cells. To identify the underlying molecular changes, we performed high-throughput RNA-sequencing of E16.5 Mafg−/−:Mafk−/− lenses and identified a cohort of differentially expressed genes that were further prioritized using stringent filtering criteria and validated by RT-qPCR. Several key factors associated with the cytoskeleton, cell cycle or extracellular matrix (e.g., Cdk1, Cdkn1c, Camsap1, Col3a1, Map3k12, Sipa1l1) were mis-expressed in Mafg−/−:Mafk−/− lenses. Further, the congenital cataract-linked extracellular matrix peroxidase Pxdn was significantly overexpressed in Mafg−/−:Mafk−/− lenses, which may cause abnormal cell morphology. These data also identified the ephrin signaling receptor Epha5 to be reduced in Mafg−/−:Mafk−/− lenses. This likely contributes to the Mafg−/−:Mafk−/− multilayered lens epithelium pathology, as loss of an ephrin ligand, Efna5 (ephrin-A5), causes similar lens defects. Together, these findings uncover a novel early function of Mafg and Mafk in lens development and identify their new downstream regulatory relationships with key cellular factors.https://www.frontiersin.org/articles/10.3389/fcell.2022.981893/fulllensMAFGMAFKtranscriptiondevelopmentepithelium |
| spellingShingle | Shaili D. Patel Deepti Anand Hozumi Motohashi Fumiki Katsuoka Masayuki Yamamoto Salil A. Lachke Salil A. Lachke Deficiency of the bZIP transcription factors Mafg and Mafk causes misexpression of genes in distinct pathways and results in lens embryonic developmental defects Frontiers in Cell and Developmental Biology lens MAFG MAFK transcription development epithelium |
| title | Deficiency of the bZIP transcription factors Mafg and Mafk causes misexpression of genes in distinct pathways and results in lens embryonic developmental defects |
| title_full | Deficiency of the bZIP transcription factors Mafg and Mafk causes misexpression of genes in distinct pathways and results in lens embryonic developmental defects |
| title_fullStr | Deficiency of the bZIP transcription factors Mafg and Mafk causes misexpression of genes in distinct pathways and results in lens embryonic developmental defects |
| title_full_unstemmed | Deficiency of the bZIP transcription factors Mafg and Mafk causes misexpression of genes in distinct pathways and results in lens embryonic developmental defects |
| title_short | Deficiency of the bZIP transcription factors Mafg and Mafk causes misexpression of genes in distinct pathways and results in lens embryonic developmental defects |
| title_sort | deficiency of the bzip transcription factors mafg and mafk causes misexpression of genes in distinct pathways and results in lens embryonic developmental defects |
| topic | lens MAFG MAFK transcription development epithelium |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2022.981893/full |
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