Quantification of gene expression patterns to reveal the origins of abnormal morphogenesis
| Autor: | Jim Swoger, Jaume Sastre Tomas, James Sharpe, Alexandre Robert-Moreno, Lucia Russo, Roger Mateu Estivill, Neus Martínez-Abadías, Susan M. Motch Perrine, Melissa Yoon, Kazuhiko Kawasaki, Joan T. Richtsmeier |
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| Přispěvatelé: | Universitat de Barcelona |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
0106 biological sciences Mouse Whole‐mount‐in‐situ hybridization (WMISH) regulación de la expresión génica medicine.disease_cause 01 natural sciences Mice biometría Gene expression Morphogenesis Optical Projection Tomography (OPT) Biology (General) Tomography Limb development Organ system 0303 health sciences Mutation whole‐mount‐in‐situ hybridization (WMISH) General Neuroscience Morfogènesi Gene Expression Regulation Developmental General Medicine Phenotype 3. Good health Medicine Developmental defects Research Article Biometry Limb defects QH301-705.5 Science Mutation Missense Apert syndrome Biology 010603 evolutionary biology General Biochemistry Genetics and Molecular Biology tomografía 03 medical and health sciences Developmental biology medicine Animals Receptor Fibroblast Growth Factor Type 2 perfiles de expresión génica mutación 030304 developmental biology Congenital diseases General Immunology and Microbiology Gene Expression Profiling Geometric Morphometrics (GM) Acrocephalosyndactylia medicine.disease Expressió gènica Mice Inbred C57BL Disease Models Animal 030104 developmental biology acrocefalosindactilia Gene Expression Regulation Evolutionary biology limb development animales Tomography X-Ray Computed ratones developmental defects Developmental Biology |
| Zdroj: | eLife, Vol 7 (2018) Recercat. Dipósit de la Recerca de Catalunya instname eLife Dipòsit Digital de la UB Universidad de Barcelona |
| Popis: | The earliest developmental origins of dysmorphologies are poorly understood in many congenital diseases. They often remain elusive because the first signs of genetic misregulation may initiate as subtle changes in gene expression, which are hard to detect and can be obscured later in development by secondary effects. Here, we develop a method to trace back the origins of phenotypic abnormalities by accurately quantifying the 3D spatial distribution of gene expression domains in developing organs. By applying Geometric Morphometrics to 3D gene expression data obtained by Optical Projection Tomography, we determined that our approach is sensitive enough to find regulatory abnormalities that have never been detected previously. We identified subtle but significant differences in the gene expression of a downstream target of a Fgfr2 mutation associated with Apert syndrome, demonstrating that these mouse models can further our understanding of limb defects in the human condition. Our method can be applied to different organ systems and models to investigate the etiology of malformations. eLife digest Our development in the womb is complex. Genes need to switch on and off in a precise order, controlling the activity of millions of cells as they work together to form different tissues. For everything to happen smoothly, cells must use instructions provided by each gene exactly at the correct moment and in the correct place. In this biological assembly line, the slightest change can lead to a defect. Certain genetic mutations can change when and where cells use particular genes, and this can cause errors in development. These kinds of mutations are a common cause of birth defects, but we cannot always pinpoint how they begin. For example, a single mutation in a gene called FGFR2 causes malformations in the head, the heart and the limbs in a rare disease called Apert syndrome. The first signs that development has gone wrong can be subtle changes in the use of certain genes, impossible to detect with standard methods. As development continues, other processes can mask the impact of problems with certain genes. Ultimately, changes alter the shape of the developing embryo. Genetically engineered mouse models can mimic the gene defects that cause disease in humans. But current methods are not sensitive enough to detect the very first signs of defects. Now, Martínez-Abadías et al. developed a new method to detect these subtle changes and reveal the precise moment when development starts to go wrong. In mice, a specific mutation in the FGFR2 gene affects the activity of a series of other genes. To track the levels of one of these genes, Martínez-Abadías et al. marked mouse embryos using a chemical label. Scanning the embryos then revealed the pattern of the cells using the gene during the earliest stages of development. In mice carrying a mutation in the FGFR2 gene, subtle changes in gene expression began just a few hours after their limbs start to develop. But it took another half a day to see the effects of these changes on the shape and size of the growing limbs. This approach revealed changes in gene expression before any problems with development were visible by eye. Tracking subtle changes in the way cells use genes could allow us to detect the origins of embryo malformations before they appear, pointing at the best moment to start a treatment. With further development, the model could extend to other genes, proteins, animal models and diseases. |
| Databáze: | OpenAIRE |
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