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Mouse model of a human neurological disorder
Genome Biology volume 2, Article number: spotlight-20010403-03 (2001)
Neurofibromatosis type 1 (NF1) is an inherited neurological disorder that affects 1 in 3,500 people worldwide. It is caused by mutations in the NF1 gene, which encodes neurofibromin, a protein involved in the Ras signalling pathway. Patients have tumours of neural origin and many have learning difficulties.
Previous attempts to knock out the NF1 gene have been unsuccessful because the mutant mice die as embryos. Now, a team of researchers led by Luis Parada of the University of Texas Southwestern Medical Center have generated mice in which an NF1 gene mutation is triggered only in neuronal cells. Reporting in the 1 April Genes and Development, Zhu et al inserted loxP sites flanking exons 31 and 32 of the mouse NF1 gene. By crossing these mice with a transgenic mouse strain that expresses Cre recombinase under the control of a neuronal-specific gene (Synapsin I), exons 31 and 32 of the NF1 gene were deleted in most differentiated neuronal populations (Genes Dev 2001, 15).
The NF1 mutant mice had severe learning defects but did not develop tumours. This suggests that the loss of NF1 in mature, differentiated neurons might not be sufficient to induce tumour development. The cerebral cortex of mutant mice was 20% smaller than in their wild-type counterparts, and there were increased numbers of astrocytes in the cortex, hippocampus and brain stem. The hyperproliferation of astrocytes, a condition known as astrogliosis, has been seen in a number of NF1 patients at post-mortem but was thought to be the result of chemotherapy. This conclusion may therefore need to be reassessed given that NF1 mutant mice also display astrogliosis.
University of Texas Southwestern Medical Center, [http://www3.utsouthwestern.edu/index.htm]
Zhu Y, Romero M, Ghosh P, Ye Z, Charnay P, Rushing EJ, Marth JD, Parada LF: Ablation of NF1 function in neurons induces abnormal development of cerebral cortex and reactive gliosis in the brain. Genes Dev 2001, 15., [http://www.genesdev.org/]
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Lee, K. Mouse model of a human neurological disorder. Genome Biol 2, spotlight-20010403-03 (2001). https://doi.org/10.1186/gb-spotlight-20010403-03
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