Loss of Aspm causes increased apoptosis of developing neural cells during mouse cerebral corticogenesis

Area of Science:

• Developmental Neuroscience
• Genetics
• Cell Biology

Background:

• Primary autosomal recessive microcephaly is linked to the Abnormal spindle-like microcephaly associated (ASPM) gene.
• The molecular mechanisms underlying microcephaly, a condition characterized by a small brain, are not fully understood.
• Neural stem and progenitor cell numbers are critical regulators of total neuron count in the developing brain.

Purpose of the Study:

• To investigate the role of the Aspm gene in fetal brain development using a brain-specific knockout mouse model.
• To elucidate the molecular mechanisms contributing to microcephaly associated with Aspm gene dysfunction.

Main Methods:

• Generation of brain-specific Aspm knockout mice.
• Evaluation of fetal brain phenotype, focusing on cortical development.
• Analysis of neural progenitor cell proliferation, neurogenesis, and apoptosis during cortical development.
• Assessment of DNA damage in neural progenitor cells.

Main Results:

• Aspm knockout mice exhibited reduced cortical size in late-stage murine cortical development.
• No significant changes were observed in neural progenitor cell proliferation or the number of newly generated neurons.
• A consistent increase in apoptosis of neural progenitor cells was detected throughout cortical development in knockout mice.
• Apoptosis in neural progenitor cells was associated with DNA damage.

Conclusions:

• Apoptosis of neural progenitor cells, triggered by DNA damage, is a key factor in the thinning of the cerebral cortex in Aspm-deficient mice.
• This study identifies increased apoptosis as a significant mechanism contributing to microcephaly resulting from Aspm gene loss during neocortical development.