Programmed cell death without DNA fragmentation in the jimpy mouse: secreted factors can enhance survival
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Published on: August 21, 2013
P E Knapp1, W P Bartlett, L A Williams
1Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky, USA.
Abstract:
Jimpy is one of many related mutations affecting the myelin proteolipid protein gene that causes severe hypomyelination in the central nervous system (CNS). Underlying the hypomyelination is a failure of oligodendrocytes (OLs) to differentiate, and the premature death of large numbers of OLs during the developmental period. Previous light and electron microscopic evidence suggested that jimpy OLs die in a manner consistent with programmed cell death. We have used TUNEL staining as a biochemical marker for apoptosis in conjunction with immunostaining for OL and myelin markers. At 13 - 14 days postnatal, a time when the number of dying OLs in jimpy CNS is increased more than five times normal, there are only modest increases (70% in spinal cord; 20% in cerebral cortex) in TUNEL labeled cells in mutant CNS tissues. The results in vitro are similar, and only a small per cent of TUNEL labeled cells have the antigenic phenotype of OLs. The discrepancy between numbers of dying and TUNEL labeled cells suggests either that most jimpy OLs do not undergo programmed cell death or that the biochemical pathways leading to their death do not involve DNA fragmentation which is detected by the TUNEL method. We also present evidence that jimpy OLs show increased survival and enhanced differentiation when they are grown in vitro in medium conditioned by cells lines which express products of the proteolipid protein gene. Cell lines expressing proteolipid protein and the alternatively spliced DM20 protein have differential effects on cell numbers and production of myelin-like membranes.
Insights
The jimpy mutation causes severe central nervous system (CNS) hypomyelination due to oligodendrocyte death. Most dying oligodendrocytes in jimpy mice do not show DNA fragmentation, suggesting alternative cell death pathways.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- The jimpy mutation in the myelin proteolipid protein gene leads to severe hypomyelination in the central nervous system (CNS).
- This hypomyelination is characterized by oligodendrocyte (OL) differentiation failure and premature OL death during development.
- Previous studies suggested jimpy OLs undergo programmed cell death.
Purpose of the Study:
- To investigate the mechanism of oligodendrocyte death in the jimpy mouse model.
- To determine if DNA fragmentation, a marker of apoptosis, is involved in jimpy OL death.
- To explore the effects of proteolipid protein (PLP) gene products on jimpy OL survival and differentiation.
Main Methods:
- TUNEL staining to detect DNA fragmentation (apoptosis).
- Immunostaining for oligodendrocyte and myelin markers.
- In vitro culture of jimpy OLs in conditioned medium from cell lines expressing PLP gene products.
Main Results:
- A significant increase in dying OLs in jimpy CNS at postnatal day 13-14, but only a modest increase in TUNEL-labeled cells.
- Similar discrepancies observed in vitro, with few TUNEL-labeled cells exhibiting OL markers.
- Jimpy OLs demonstrated increased survival and differentiation in vitro when cultured in medium conditioned by PLP-expressing cell lines.
- Cell lines expressing PLP and DM20 showed differential effects on OL numbers and myelin production.
Conclusions:
- The majority of dying jimpy oligodendrocytes may not undergo apoptosis via DNA fragmentation, suggesting alternative cell death pathways.
- Proteolipid protein gene products can promote jimpy oligodendrocyte survival and differentiation.
- These findings provide insights into the cellular mechanisms underlying jimpy hypomyelination and potential therapeutic targets.
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