Dysregulated H19/Igf2 expression disrupts cardiac-placental axis during development of Silver-Russell syndrome-like mouse models
Dysregulation of the imprinted H19/IGF2 locus can lead to Silver-Russell syndrome (SRS) in humans. However, the mechanism of how abnormal H19/IGF2 expression contributes to various SRS phenotypes remains unclear, largely due to incomplete understanding of the developmental functions of these two gen...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-11-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/78754 |
| _version_ | 1811215506463522816 |
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| author | Suhee Chang Diana Fulmer Stella K Hur Joanne L Thorvaldsen Li Li Yemin Lan Eric A Rhon-Calderon Nicolae Adrian Leu Xiaowen Chen Jonathan A Epstein Marisa S Bartolomei |
| author_facet | Suhee Chang Diana Fulmer Stella K Hur Joanne L Thorvaldsen Li Li Yemin Lan Eric A Rhon-Calderon Nicolae Adrian Leu Xiaowen Chen Jonathan A Epstein Marisa S Bartolomei |
| author_sort | Suhee Chang |
| collection | DOAJ |
| description | Dysregulation of the imprinted H19/IGF2 locus can lead to Silver-Russell syndrome (SRS) in humans. However, the mechanism of how abnormal H19/IGF2 expression contributes to various SRS phenotypes remains unclear, largely due to incomplete understanding of the developmental functions of these two genes. We previously generated a mouse model with humanized H19/IGF2 imprinting control region (hIC1) on the paternal allele that exhibited H19/Igf2 dysregulation together with SRS-like growth restriction and perinatal lethality. Here, we dissect the role of H19 and Igf2 in cardiac and placental development utilizing multiple mouse models with varying levels of H19 and Igf2. We report severe cardiac defects such as ventricular septal defects and thinned myocardium, placental anomalies including thrombosis and vascular malformations, together with growth restriction in mouse embryos that correlated with the extent of H19/Igf2 dysregulation. Transcriptomic analysis using cardiac endothelial cells of these mouse models shows that H19/Igf2 dysregulation disrupts pathways related to extracellular matrix and proliferation of endothelial cells. Our work links the heart and placenta through regulation by H19 and Igf2, demonstrating that accurate dosage of both H19 and Igf2 is critical for normal embryonic development, especially related to the cardiac-placental axis. |
| first_indexed | 2024-04-12T06:23:43Z |
| format | Article |
| id | doaj.art-6e1ce1ff28534687a37e77cf4367e911 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T06:23:43Z |
| publishDate | 2022-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-6e1ce1ff28534687a37e77cf4367e9112022-12-22T03:44:13ZengeLife Sciences Publications LtdeLife2050-084X2022-11-011110.7554/eLife.78754Dysregulated H19/Igf2 expression disrupts cardiac-placental axis during development of Silver-Russell syndrome-like mouse modelsSuhee Chang0https://orcid.org/0000-0002-0514-3516Diana Fulmer1https://orcid.org/0000-0001-7675-9951Stella K Hur2Joanne L Thorvaldsen3Li Li4Yemin Lan5Eric A Rhon-Calderon6Nicolae Adrian Leu7Xiaowen Chen8Jonathan A Epstein9https://orcid.org/0000-0001-8637-4465Marisa S Bartolomei10https://orcid.org/0000-0001-9410-5222Department of Cell and Developmental Biology, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United StatesDepartment of Cell and Developmental Biology, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States; Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United StatesDepartment of Cell and Developmental Biology, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United StatesDepartment of Cell and Developmental Biology, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United StatesDepartment of Cell and Developmental Biology, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States; Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United StatesDepartment of Cell and Developmental Biology, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United StatesDepartment of Cell and Developmental Biology, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United StatesDepartment of Biomedical Sciences, School of Veterinary Medicine, Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, United StatesPenn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United StatesDepartment of Cell and Developmental Biology, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States; Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United StatesDepartment of Cell and Developmental Biology, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United StatesDysregulation of the imprinted H19/IGF2 locus can lead to Silver-Russell syndrome (SRS) in humans. However, the mechanism of how abnormal H19/IGF2 expression contributes to various SRS phenotypes remains unclear, largely due to incomplete understanding of the developmental functions of these two genes. We previously generated a mouse model with humanized H19/IGF2 imprinting control region (hIC1) on the paternal allele that exhibited H19/Igf2 dysregulation together with SRS-like growth restriction and perinatal lethality. Here, we dissect the role of H19 and Igf2 in cardiac and placental development utilizing multiple mouse models with varying levels of H19 and Igf2. We report severe cardiac defects such as ventricular septal defects and thinned myocardium, placental anomalies including thrombosis and vascular malformations, together with growth restriction in mouse embryos that correlated with the extent of H19/Igf2 dysregulation. Transcriptomic analysis using cardiac endothelial cells of these mouse models shows that H19/Igf2 dysregulation disrupts pathways related to extracellular matrix and proliferation of endothelial cells. Our work links the heart and placenta through regulation by H19 and Igf2, demonstrating that accurate dosage of both H19 and Igf2 is critical for normal embryonic development, especially related to the cardiac-placental axis.https://elifesciences.org/articles/78754H19Igf2SRScardiac-placental axiscardiac developmentendothelial cells |
| spellingShingle | Suhee Chang Diana Fulmer Stella K Hur Joanne L Thorvaldsen Li Li Yemin Lan Eric A Rhon-Calderon Nicolae Adrian Leu Xiaowen Chen Jonathan A Epstein Marisa S Bartolomei Dysregulated H19/Igf2 expression disrupts cardiac-placental axis during development of Silver-Russell syndrome-like mouse models eLife H19 Igf2 SRS cardiac-placental axis cardiac development endothelial cells |
| title | Dysregulated H19/Igf2 expression disrupts cardiac-placental axis during development of Silver-Russell syndrome-like mouse models |
| title_full | Dysregulated H19/Igf2 expression disrupts cardiac-placental axis during development of Silver-Russell syndrome-like mouse models |
| title_fullStr | Dysregulated H19/Igf2 expression disrupts cardiac-placental axis during development of Silver-Russell syndrome-like mouse models |
| title_full_unstemmed | Dysregulated H19/Igf2 expression disrupts cardiac-placental axis during development of Silver-Russell syndrome-like mouse models |
| title_short | Dysregulated H19/Igf2 expression disrupts cardiac-placental axis during development of Silver-Russell syndrome-like mouse models |
| title_sort | dysregulated h19 igf2 expression disrupts cardiac placental axis during development of silver russell syndrome like mouse models |
| topic | H19 Igf2 SRS cardiac-placental axis cardiac development endothelial cells |
| url | https://elifesciences.org/articles/78754 |
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