Abstract
We describe a novel spontaneous mouse mutant, laggard (lag), characterized by a flat head, motor impairment and growth retardation. The mutation is inherited as an autosomal recessive trait, and lag/lag mice suffer from cerebellar ataxia and die before weaning. lag/lag mice exhibit a dramatic reduction in brain size and slender optic nerves. By positional cloning, we identify a splice site mutation in Kif14. Transgenic complementation with wild-type Kif14-cDNA alleviates ataxic phenotype in lag/lag mice. To further confirm that the causative gene is Kif14, we generate Kif14 knockout mice and find that all of the phenotypes of Kif14 knockout mice are similar to those of lag/lag mice. The main morphological abnormality of lag/lag mouse is severe hypomyelination in central nervous system. The lag/lag mice express an array of myelin-related genes at significantly reduced levels. The disrupted cytoarchitecture of the cerebellar and cerebral cortices appears to result from apoptotic cell death. Thus, we conclude that Kif14 is essential for the generation and maturation of late-developing structures such as the myelin sheath, cerebellar and cerebral cortices. So far, no Kif14-deficient mice or mutation in Kif14 has ever been reported and we firstly define the biological function of Kif14 in vivo. The discovery of mammalian models, laggard, has opened up horizons for researchers to add more knowledge regarding the etiology and pathology of brain malformation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Transport Systems, Acidic / deficiency
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Amino Acid Transport Systems, Acidic / genetics
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Amino Acid Transport Systems, Acidic / metabolism
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Animals
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Antiporters / deficiency
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Antiporters / genetics
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Antiporters / metabolism
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Apoptosis
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Base Sequence
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Cerebellar Ataxia / genetics*
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Cerebellar Ataxia / metabolism
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Cerebellar Ataxia / pathology
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Cerebellum / metabolism
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Cerebellum / pathology*
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Cerebral Cortex / metabolism
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Cerebral Cortex / pathology*
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Female
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Genetic Complementation Test
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Hereditary Central Nervous System Demyelinating Diseases / genetics*
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Hereditary Central Nervous System Demyelinating Diseases / metabolism
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Hereditary Central Nervous System Demyelinating Diseases / pathology
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Kinesins / genetics*
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Male
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Mice
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Mice, Transgenic
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Mitochondrial Diseases / genetics*
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Mitochondrial Diseases / metabolism
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Mitochondrial Diseases / pathology
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Molecular Sequence Data
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Mutation*
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Myelin Sheath / genetics*
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Myelin Sheath / metabolism
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Myelin Sheath / pathology
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Phenotype
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Protein Isoforms / genetics
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Psychomotor Disorders / genetics*
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Psychomotor Disorders / metabolism
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Psychomotor Disorders / pathology
Substances
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Amino Acid Transport Systems, Acidic
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Antiporters
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Protein Isoforms
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Kif14 protein, mouse
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Kinesins
Supplementary concepts
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Hypomyelination, Global Cerebral
Grants and funding
This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (number 22500334), by a grant provided by The Japan Epilepsy Research Foundation, and by the grant provided by Takeda Science Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.