Animal models of β-hemoglobinopathies: utility and limitations
Bradley McColl, Jim Vadolas Cell and Gene Therapy Laboratory, Murdoch Childrens Research Institute, Royal Children’s Hospital, Parkville, VIC, Australia Abstract: The structural and functional conservation of hemoglobin throughout mammals has made the laboratory mouse an exception...
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| Format: | Article |
| Language: | English |
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Dove Medical Press
2016-11-01
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| Series: | Journal of Blood Medicine |
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| Online Access: | https://www.dovepress.com/animal-models-of-beta-hemoglobinopathies-utility-and-limitations-peer-reviewed-article-JBM |
| _version_ | 1818140833639038976 |
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| author | McColl B Vadolas J |
| author_facet | McColl B Vadolas J |
| author_sort | McColl B |
| collection | DOAJ |
| description | Bradley McColl, Jim Vadolas Cell and Gene Therapy Laboratory, Murdoch Childrens Research Institute, Royal Children’s Hospital, Parkville, VIC, Australia Abstract: The structural and functional conservation of hemoglobin throughout mammals has made the laboratory mouse an exceptionally useful organism in which to study both the protein and the individual globin genes. Early researchers looked to the globin genes as an excellent model in which to examine gene regulation – bountifully expressed and displaying a remarkably consistent pattern of developmental activation and silencing. In parallel with the growth of research into expression of the globin genes, mutations within the β-globin gene were identified as the cause of the β-hemoglobinopathies such as sickle cell disease and β-thalassemia. These lines of enquiry stimulated the development of transgenic mouse models, first carrying individual human globin genes and then substantial human genomic fragments incorporating the multigenic human β-globin locus and regulatory elements. Finally, mice were devised carrying mutant human β-globin loci on genetic backgrounds deficient in the native mouse globins, resulting in phenotypes of sickle cell disease or β-thalassemia. These years of work have generated a group of model animals that display many features of the β-hemoglobinopathies and provided enormous insight into the mechanisms of gene regulation. Substantive differences in the expression of human and mouse globins during development have also come to light, revealing the limitations of the mouse model, but also providing opportunities to further explore the mechanisms of globin gene regulation. In addition, animal models of β-hemoglobinopathies have demonstrated the feasibility of gene therapy for these conditions, now showing success in human clinical trials. Such models remain in use to dissect the molecular events of globin gene regulation and to identify novel treatments based upon the reactivation of developmentally silenced γ-globin. Here, we describe the development of animal models to investigate globin switching and the β-hemoglobinopathies, a field that has paralleled the emergence of modern molecular biology and clinical genetics. Keywords: β-Hemoglobinopathies, sickle cell disease, globin switching, locus control region, bacterial artificial chromosome, green fluorescent protein |
| first_indexed | 2024-12-11T10:50:16Z |
| format | Article |
| id | doaj.art-bde2d99de90f4b6c8d040cf94bf025cc |
| institution | Directory Open Access Journal |
| issn | 1179-2736 |
| language | English |
| last_indexed | 2024-12-11T10:50:16Z |
| publishDate | 2016-11-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Journal of Blood Medicine |
| spelling | doaj.art-bde2d99de90f4b6c8d040cf94bf025cc2022-12-22T01:10:19ZengDove Medical PressJournal of Blood Medicine1179-27362016-11-01Volume 726327429858Animal models of β-hemoglobinopathies: utility and limitationsMcColl BVadolas JBradley McColl, Jim Vadolas Cell and Gene Therapy Laboratory, Murdoch Childrens Research Institute, Royal Children’s Hospital, Parkville, VIC, Australia Abstract: The structural and functional conservation of hemoglobin throughout mammals has made the laboratory mouse an exceptionally useful organism in which to study both the protein and the individual globin genes. Early researchers looked to the globin genes as an excellent model in which to examine gene regulation – bountifully expressed and displaying a remarkably consistent pattern of developmental activation and silencing. In parallel with the growth of research into expression of the globin genes, mutations within the β-globin gene were identified as the cause of the β-hemoglobinopathies such as sickle cell disease and β-thalassemia. These lines of enquiry stimulated the development of transgenic mouse models, first carrying individual human globin genes and then substantial human genomic fragments incorporating the multigenic human β-globin locus and regulatory elements. Finally, mice were devised carrying mutant human β-globin loci on genetic backgrounds deficient in the native mouse globins, resulting in phenotypes of sickle cell disease or β-thalassemia. These years of work have generated a group of model animals that display many features of the β-hemoglobinopathies and provided enormous insight into the mechanisms of gene regulation. Substantive differences in the expression of human and mouse globins during development have also come to light, revealing the limitations of the mouse model, but also providing opportunities to further explore the mechanisms of globin gene regulation. In addition, animal models of β-hemoglobinopathies have demonstrated the feasibility of gene therapy for these conditions, now showing success in human clinical trials. Such models remain in use to dissect the molecular events of globin gene regulation and to identify novel treatments based upon the reactivation of developmentally silenced γ-globin. Here, we describe the development of animal models to investigate globin switching and the β-hemoglobinopathies, a field that has paralleled the emergence of modern molecular biology and clinical genetics. Keywords: β-Hemoglobinopathies, sickle cell disease, globin switching, locus control region, bacterial artificial chromosome, green fluorescent proteinhttps://www.dovepress.com/animal-models-of-beta-hemoglobinopathies-utility-and-limitations-peer-reviewed-article-JBMβ-hemoglobinopathies Mouse models |
| spellingShingle | McColl B Vadolas J Animal models of β-hemoglobinopathies: utility and limitations Journal of Blood Medicine β-hemoglobinopathies Mouse models |
| title | Animal models of β-hemoglobinopathies: utility and limitations |
| title_full | Animal models of β-hemoglobinopathies: utility and limitations |
| title_fullStr | Animal models of β-hemoglobinopathies: utility and limitations |
| title_full_unstemmed | Animal models of β-hemoglobinopathies: utility and limitations |
| title_short | Animal models of β-hemoglobinopathies: utility and limitations |
| title_sort | animal models of beta hemoglobinopathies utility and limitations |
| topic | β-hemoglobinopathies Mouse models |
| url | https://www.dovepress.com/animal-models-of-beta-hemoglobinopathies-utility-and-limitations-peer-reviewed-article-JBM |
| work_keys_str_mv | AT mccollb animalmodelsofbetahemoglobinopathiesutilityandlimitations AT vadolasj animalmodelsofbetahemoglobinopathiesutilityandlimitations |