Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1
| Autor: | Jun-Lin Guan, Yuan Wang, Emmanuelle S. Jecrois, Yuan Zhu, Chenran Wang, Todd E. Anthony, Yi E. Li, Geoffrey G. Murphy, Sun-Jung Kim, Miriam Bornhorst, Edward Y. Kim |
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| Rok vydání: | 2014 |
| Předmět: |
MAPK/ERK pathway
granule cell Cerebellum Mice 0302 clinical medicine bergmann glial cell Biology (General) tumor suppressor gene Extracellular Signal-Regulated MAP Kinases Neurons 0303 health sciences General Neuroscience unipolar brush cells General Medicine Anatomy 3. Good health medicine.anatomical_structure Medicine Research Article congenital hereditary and neonatal diseases and abnormalities cerebellum Neurofibromatoses QH301-705.5 Science Biology neurofibromatosis type 1 General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Glutamatergic bergmann glial cells Genes Neurofibromatosis 1 medicine Animals Learning Gene silencing Gene Silencing Neurofibromatosis mouse Alleles Cell Proliferation 030304 developmental biology General Immunology and Microbiology Granule cell medicine.disease Disease Models Animal Developmental Biology and Stem Cells nervous system Astrocytes Unipolar brush cell unipolar brush cell Developmental biology Neuroscience granule cells Psychomotor Performance 030217 neurology & neurosurgery |
| Zdroj: | eLife eLife, Vol 3 (2014) |
| ISSN: | 2050-084X |
| DOI: | 10.7554/elife.05151 |
| Popis: | Individuals with neurofibromatosis type 1 (NF1) frequently exhibit cognitive and motor impairments and characteristics of autism. The cerebellum plays a critical role in motor control, cognition, and social interaction, suggesting that cerebellar defects likely contribute to NF1-associated neurodevelopmental disorders. Here we show that Nf1 inactivation during early, but not late stages of cerebellar development, disrupts neuronal lamination, which is partially caused by overproduction of glia and subsequent disruption of the Bergmann glia (BG) scaffold. Specific Nf1 inactivation in glutamatergic neuronal precursors causes premature differentiation of granule cell (GC) precursors and ectopic production of unipolar brush cells (UBCs), indirectly disrupting neuronal migration. Transient MEK inhibition during a neonatal window prevents cerebellar developmental defects and improves long-term motor performance of Nf1-deficient mice. This study reveals essential roles of Nf1 in GC/UBC migration by generating correct numbers of glia and controlling GC/UBC fate-specification/differentiation, identifying a therapeutic prevention strategy for multiple NF1-associcated developmental abnormalities. DOI: http://dx.doi.org/10.7554/eLife.05151.001 eLife digest Neurofibromatosis type 1 is a condition characterized by the growth of tumors along the nerves of the body. It is caused by mutations in a gene called NF1, which codes for a protein that normally works to inhibit the activity of another protein called Ras. In healthy cells, Ras is needed to stimulate the cells to grow and divide. However, if the Ras protein is not turned off at the right time or if it is activated at the wrong time, it can force cells to keep growing and dividing; this leads to the growth of tumors. Along with being prone to developing cancer, individuals with neurofibromatosis type 1 also develop a range of neurodevelopmental disorders that alter their learning, motor skills and social interactions. Some also exhibit behaviors that are associated with autism. This led Kim, Wang et al. to investigate whether a region of the brain—called the cerebellum—that has recently been associated with autism is also affected in a mouse model of neurofibromatosis type 1. The cerebellum is best known for its role in coordinating movement, although it also has functions in cognition, behavior and other processes. Ras is involved in the development of the cerebellum; and so Kim, Wang et al. asked whether the loss of the Nf1 gene from cells in the mouse cerebellum might cause the neurodevelopmental defects associated with neurofibromatosis type 1. Loss of Nf1 during early (but not in late) development of the cerebellum disrupted the normal organization of the nerve cells (or neurons) into specific cell layers. These defects were caused, in part, by the over-growth of a type of supporting cell—called glia cells—at a specific developmental stage—that would normally form a scaffold to help neurons migrate to their correct position. Nf1 also controls the generation of the correct types of neurons in the right time and at right location during the early development of the cerebellum. Next, Kim, Wang et al. treated newborn mice with a compound that inhibits Ras signaling via their mother's milk for 3 weeks. In mice with an inactive Nf1 gene, the treatment helped to prevent some defects in the cerebellum and the mice had improved motor coordination several months later. Whether this could form the basis of a preventative treatment for neurodevelopmental disorders associated with neurofibromatosis type 1 in humans remains a question for future work. DOI: http://dx.doi.org/10.7554/eLife.05151.002 |
| Databáze: | OpenAIRE |
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