Failure of central nervous system myelination in MBP/c-myc transgenic mice: evidence for c-myc cytotoxicity

Area of Science:

• Neuroscience
• Molecular Biology
• Oncology

Background:

• The c-myc oncogene, a helix-loop-helix/leucine zipper protein, regulates gene transcription.
• Aberrant c-myc expression is implicated in astrocytic glioma carcinogenesis.
• The specific effects of c-myc expression on oligodendrocytes remain largely unknown.

Purpose of the Study:

• To investigate the impact of c-myc oncogene overexpression in oligodendrocytes.
• To utilize transgenic mice with c-myc under the control of the myelin basic protein gene promoter.

Main Methods:

• Generation of myelin basic protein/c-myc (MBP/c-myc) transgenic mice.
• Assessment of neurological function, survival rates, and central nervous system myelination.
• Quantification of c-myc, myelin basic protein (MBP), and proteolipid protein (PLP) mRNA levels.
• TUNEL assay and double immunohistochemistry to detect apoptosis and c-myc expression in situ.

Main Results:

• MBP/c-myc transgenic mice exhibited severe neurological disturbances, including tremors and seizures, leading to premature death.
• Affected mice displayed significantly hypomyelinated central nervous systems with reduced MBP and PLP mRNA.
• Increased TUNEL-positive nuclei were observed in c-myc expressing cells, indicating apoptosis.
• No brain tumors were detected in any c-myc transgenic mice, including heterozygous individuals.

Conclusions:

• Overexpression of the c-myc oncogene in oligodendrocytes induces a cytotoxic effect, leading to myelin deficiency.
• The observed hypomyelination is a result of c-myc-induced cell death, not oncogenesis.
• These findings highlight a critical role for c-myc in oligodendrocyte survival and myelination.