| RRC ID |
85010
|
| Author |
Mori T, Zhou M, Kunugitani K, Akatsuka T, Yoshida Y, Kouyama-Suzuki E, Kobayashi S, Shirai Y, Tabuchi K.
|
| Title |
The Competitive Loss of Cerebellar Granule and Purkinje Cells Driven by X-Linked Mosaicism in a Female Mouse Model of CASK-Related Disorders.
|
| Journal |
Cells
|
| Abstract |
CASK-related disorders are a form of female-restricted intellectual disabilities associated with cerebellar and pontine hypoplasia. The CASK gene is regulated by X-chromosome inactivation, which results in a mosaic distribution of CASK-expressing and CASK-deficient neurons in the female brain. This mosaic distribution is believed to play a key role in the pathophysiology of X-linked neurological disorders; however, the detailed brain structure has not been extensively characterized. In this study, we used CASK heterozygous knockout (CASK-hKO) mice combined with X-linked GFP reporter mice to investigate motor abilities and the distribution of CASK-expressing cells in the brains of female CASK-hKO mice. The CASK-hKO mice exhibited motor deficits and cerebellar hypoplasia similar to those observed in patients with CASK-related disorders. Interestingly, although half of the cerebellar granule cells were CASK-negative during early postnatal development, almost all Purkinje cells and cerebellar granule cells were CASK-positive in adulthood, suggesting that CASK expression may determine the survival of cerebellar granule cells during postnatal development. We also analyzed CASK-hypomorphic mice, which express 50% less CASK than wild-type mice, and compared hemizygous males and heterozygous females. The CASK-hypomorphic heterozygous females displayed a thinner cerebellar cortex and a higher probability of CASK-positive granule cells in CASK-hKO females, suggesting that the survival of cerebellar granule cells is regulated by a combination of cell-autonomous and cell-competitive mechanisms between CASK-expressing and CASK-deficient cells, which are generated by X-chromosome inactivation. These findings provide new insights into the relationship between the mosaic distribution of cells established by X-chromosome inactivation and the pathophysiology of CASK-related disorders.
|
| Volume |
14(10)
|
| Published |
2025-5-17
|
| DOI |
10.3390/cells14100735
|
| PII |
cells14100735
|
| PMID |
40422238
|
| PMC |
PMC12109812
|
| MeSH |
Animals
Cerebellum* / metabolism
Cerebellum* / pathology
Disease Models, Animal
Female
Guanylate Kinases* / deficiency
Guanylate Kinases* / genetics
Guanylate Kinases* / metabolism
Male
Mice
Mice, Knockout
Mosaicism*
Purkinje Cells* / metabolism
Purkinje Cells* / pathology
X Chromosome Inactivation
|
| IF |
4.366
|
| Resource |
| Mice |
RBRC09532 |
