Disruption of Aspm causes microcephaly with abnormal neuronal differentiation
Akira Fujimori1, Kyoko Itoh2, Shoko Goto2
1Heavy-Ion Radiobiology Research Group, Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan.
Aims:
A number of ASPM mutations have been detected in primary microcephaly patients. In order to evaluate the function of ASPM in brain development, we generated model animals of human autosomal recessive primary microcephaly-5 (MCPH5).
Methods:
In the Aspm knock-out mice, the exon 2-3 of the Aspm gene was encompassed by a pair of loxP signals so that cre-recombinase activity switched the allele from wild-type to null zygotes as frequently, as expected from the Mendelian inheritance. We precisely analyzed the brains of adults and fetuses using immunohistochemistry and morphometry.
Results:
The adult brains of the Aspm(-/-) mice were smaller, especially in the cerebrum. In the barrel field of the somatosensory cortex, layer I was significantly thicker, whereas layer VI was significantly thinner in Aspm(-/-) mice, compared with Aspm(+/+) mice. The total number of cells and the thickness of the cortical plate at embryonic day 16.5 was significantly decreased in Aspm(-/-) mice, compared with Aspm(+/+) mice. Furthermore, the expression of transcription factors, such as Tbr1 and Satb2, was significantly increased in the subplate of the Aspm(-/-) mice.
Conclusions:
The results suggested that Aspm is essential to the proliferation and differentiation of neural stem/progenitor cells. The Aspm gene loss model provided a novel pathogenetic insight into acquired microcephaly, which can be caused by in utero exposure to both known and unknown teratogens.
Insights
ASPM gene mutations cause primary microcephaly. Aspm knockout mice showed smaller brains and altered cortical development, indicating ASPM is crucial for neural stem/progenitor cell proliferation and differentiation.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Mutations in the ASPM gene are linked to primary microcephaly, a condition characterized by reduced brain size.
- Understanding ASPM's role is crucial for elucidating the pathogenesis of microcephaly.
Purpose of the Study:
- To investigate the function of ASPM in brain development using a mouse model of human autosomal recessive primary microcephaly-5 (MCPH5).
Main Methods:
- Generated Aspm knock-out mice by flanking exons 2-3 with loxP sites for cre-recombinase mediated deletion.
- Analyzed adult and fetal brains using immunohistochemistry and morphometry.
Main Results:
- Aspm(-/-) mice exhibited smaller brains, particularly the cerebrum.
- Significant alterations in cortical layer thickness (thicker layer I, thinner layer VI) and reduced cortical plate thickness and cell number at E16.5 were observed.
- Increased expression of Tbr1 and Satb2 in the subplate of Aspm(-/-) mice.
Conclusions:
- ASPM is essential for the proliferation and differentiation of neural stem and progenitor cells.
- This Aspm gene loss model offers insights into the development of microcephaly, potentially linked to in utero teratogen exposure.
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