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The megencephaly mouse has disturbances in the insulin-like growth factor (IGF) system
S Petersson1, A Sandberg Nordqvist, M Schalling
1Neurogenetics Unit, Center for Molecular Medicine, Karolinska Institutet, L8:00, 171 76, Stockholm, Sweden.
Abstract:
Megencephaly, enlarged brain, is a major sign in several human neurological diseases. The mouse model for megencephaly, mceph/mceph, has an enlarged brain and a lowered body weight. In addition, it displays several neurological and motoric disturbances. Previous studies suggest that the brain enlargement results from hypertrophy of the brain cells, rather than hyperplasia. No structural abnormalities, edema or increased myelination have been found. In this study, a major imbalance in the mRNA expression of molecules in the insulin-like growth factor (IGF) system was found in brains of 9-10 weeks old mceph/mceph mice compared to +/+ wild-type mice. In mceph/mceph brains, we found upregulation of IGF binding proteins (BP)-2, -4, -5, and -6 mRNA, the regulating hormone transforming growth factor (TGF)beta1 mRNA and also a local downregulation of IGFBP-5 mRNA compared to wild-type brains by in situ hybridization. The altered expression of these mRNA species is colocalized in cerebral cortex, hippocampus, amygdala and piriform/entorhinal cortex. The mceph/mceph mice express less of the myelin component proteolipid protein (PLP) mRNA in corpus callosum. No expression difference of the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in brain or IGF system components in liver was found between mceph/mceph and wild-type mice. These data suggest that the IGF system has an important role in the excessive growth of the mceph/mceph brains.
Insights
The mceph/mceph mouse model exhibits an enlarged brain, a condition known as megencephaly. This study reveals significant alterations in the insulin-like growth factor (IGF) system
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Megencephaly, or enlarged brain, is a hallmark of several human neurological disorders.
- The mceph/mceph mouse model displays enlarged brains, reduced body weight, and neurological/motor deficits.
- Previous research indicates brain enlargement in this model is due to cell hypertrophy, not hyperplasia, with no structural abnormalities observed.
Purpose of the Study:
- To investigate the role of the insulin-like growth factor (IGF) system in the enlarged brain phenotype of mceph/mceph mice.
- To identify specific molecular changes within the IGF system in the brains of mceph/mceph mice.
Main Methods:
- Comparative analysis of mRNA expression in the brains of mceph/mceph mice and wild-type littermates (+/+).
- Utilized in situ hybridization to examine the spatial distribution of specific mRNA species.
- Focused on key brain regions including the cerebral cortex, hippocampus, amygdala, and piriform/entorhinal cortex.
Main Results:
- Significant imbalance in mRNA expression of IGF system components in mceph/mceph brains.
- Upregulation of IGF binding proteins (BP)-2, -4, -5, and -6 mRNA, and transforming growth factor (TGF)beta1 mRNA.
- Downregulation of IGFBP-5 mRNA and proteolipid protein (PLP) mRNA in the corpus callosum of mceph/mceph mice.
- No significant changes in the housekeeping gene GAPDH or hepatic IGF system components.
Conclusions:
- The insulin-like growth factor (IGF) system plays a crucial role in the excessive brain growth observed in the mceph/mceph mouse model.
- Altered expression patterns of IGF system molecules are localized to specific brain regions affected by megencephaly.
- These findings provide insights into the molecular mechanisms underlying IGF-mediated brain development and disease.