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Development of the cerebellar defect in ataxic SELH/Bc mice
M J Harris1, D M Juriloff, T M Gunn
1Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
Insights
Cerebellar midline clefts in SELH/Bc mice result from delayed cranial neural tube closure. This defect, observed in embryos and fetuses, leads to ataxia in young adults.
Area of Science:
- Developmental biology
- Neuroscience
- Genetics
Background:
- SELH/Bc mice exhibit ataxia linked to cerebellar midline clefts in 5-10% of young adults.
- A subset of SELH/Bc embryos also display exencephaly, leading to perinatal mortality.
- All SELH/Bc embryos show a failure in cranial neural tube closure at the Closure 2 stage.
Purpose of the Study:
- To investigate the hypothesis that delayed cerebellar neural tube closure causes the midline cleft in SELH/Bc mice.
- To identify the earliest developmental stage at which the cerebellar midline cleft defect is detectable.
Main Methods:
- Histological examination of SELH/Bc embryos and fetuses at various developmental stages (D10, D11, D16).
- Assessment of cerebellar neuroepithelium continuity and midline fusion.
- Comparison of cerebellar morphology in affected SELH/Bc mice with Wnt-1 mutants.
Main Results:
- A cerebellar midline cleft was detected in 7-9% of SELH/Bc D16 fetuses and D11 embryos.
- The defect was observable as early as D10 in SELH/Bc embryos.
- Affected specimens showed a gap in the midline continuity of the cerebellar neuroepithelium, supporting failed fusion.
Conclusions:
- The findings support the hypothesis that delayed closure of the prospective cerebellar region during neural tube development leads to midline clefts.
- This developmental delay is the primary cause of ataxia in adult SELH/Bc mice.
- Unlike Wnt-1 mutants, the SELH/Bc cerebellar defect does not involve lobule deficiency or tissue disorganization.
Abstract:
In SELH/Bc mice, 5-10% of young adults are ataxic, due to a midline cleft in the cerebellum. An additional 10-20% of SELH/Bc embryos have exencephaly and die at birth. All SELH/Bc embryos omit a normal step in cranial neural tube closure, initiation of fusion at Closure 2. In the 80-90% that complete cranial neural tube closure, the last region of closure, on late D9, is the region of the prospective cerebellum, and its closure is late. We postulated that the cleft cerebellum in ataxic SELH/Bc mice derives from this delay in neural tube closure and predicted that we would see evidence of a cerebellar midline cleft in all earlier stages after cranial neural tube closure is normally complete. In the present study we show that the cerebellum is cleft in a 7-9% proportion of SELH/Bc D16 fetuses (2/28) and D11 embryos (15/167), and that the defect is detectable on D10. In these abnormal D16 fetuses, D11 and D10 embryos, there is a gap in midline continuity of cerebellar neuroepithelium, a finding consistent with our hypothesis that the neuroepithelium in this region fails to complete fusion in those embryos. We also show that cerebella of adult SELH/Bc ataxic mice have no obvious deficiency of lobules, or disorganization of tissue as in the Wnt-1 mutants.