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The Jnk1 and Jnk2 protein kinases are required for regional specific apoptosis during early brain development
C Y Kuan1, D D Yang, D R Samanta Roy
1Section of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Abstract:
The c-Jun NH2-terminal kinase (Jnk) family is implicated in apoptosis, but its function in brain development is unclear. Here, we address this issue using mutant mice lacking different members of the family (Jnk1, Jnk2, and Jnk3). Mice deficient in Jnk1, Jnk2, Jnk3, and Jnk1/Jnk3 or Jnk2/Jnk3 double mutants all survived normally. Compound mutants lacking Jnk1 and Jnk2 genes were embryonic lethal and had severe dysregulation of apoptosis in brain. Specifically, there was a reduction of cell death in the lateral edges of hindbrain prior to neural tube closure. In contrast, increased apoptosis and caspase activation were found in the mutant forebrain, leading to precocious degeneration. These results suggest that Jnk1 and Jnk2 regulate region-specific apoptosis during early brain development.
Insights
The c-Jun NH2-terminal kinase (JNK) family plays a crucial role in regulating apoptosis during early brain development. JNK1 and JNK2 are essential for proper cell death in specific brain regions, preventing developmental defects.
Area of Science:
- Neuroscience
- Developmental Biology
- Cell Biology
Background:
- The c-Jun NH2-terminal kinase (JNK) signaling pathway is known to be involved in apoptosis.
- However, its specific role in mammalian brain development remains largely uncharacterized.
Purpose of the Study:
- To investigate the function of the JNK family members (JNK1, JNK2, and JNK3) in early brain development.
- To determine the role of JNK signaling in regulating apoptosis during neurodevelopment.
Main Methods:
- Utilized knockout mouse models with deficiencies in Jnk1, Jnk2, and Jnk3 genes, including single and compound mutants.
- Analyzed embryonic lethality, brain morphology, and apoptosis levels in developing brains of mutant mice.
- Assessed caspase activation as a marker for apoptosis.
Main Results:
- Mice lacking Jnk1, Jnk2, Jnk3, or double mutants (Jnk1/Jnk3, Jnk2/Jnk3) exhibited normal survival.
- Compound mutants lacking both Jnk1 and Jnk2 genes were embryonic lethal.
- These Jnk1/Jnk2 deficient mutants displayed significant dysregulation of apoptosis in the developing brain, with reduced cell death in the hindbrain and increased apoptosis and degeneration in the forebrain.
Conclusions:
- JNK1 and JNK2 play critical, region-specific roles in regulating apoptosis during early brain development.
- Disruption of JNK1 and JNK2 function leads to severe neurodevelopmental defects due to aberrant apoptosis.