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Axonal Cleaved Caspase-3 Regulates Axon Targeting and Morphogenesis in the Developing Auditory Brainstem
Sarah E Rotschafer1, Michelle R Allen-Sharpley1, Karina S Cramer1
1Department of Neurobiology and Behavior, University of California Irvine, CA, USA.
Abstract:
Caspase-3 is a cysteine protease that is most commonly associated with cell death. Recent studies have shown additional roles in mediating cell differentiation, cell proliferation and development of cell morphology. We investigated the role of caspase-3 in the development of chick auditory brainstem nuclei during embryogenesis. Immunofluorescence from embryonic days E6-13 revealed that the temporal expression of cleaved caspase-3 follows the ascending anatomical pathway. The expression is first seen in the auditory portion of VIIIth nerve including central axonal regions projecting to nucleus magnocellularis (NM), then later in NM axons projecting to nucleus laminaris (NL), and subsequently in NL dendrites. To examine the function of cleaved caspase-3 in chick auditory brainstem development, we blocked caspase-3 cleavage in developing chick embryos with the caspase-3 inhibitor Z-DEVD-FMK from E6 to E9, then examined NM and NL morphology and NM axonal targeting on E10. NL lamination in treated embryos was disorganized and the neuropil around NL contained a significant number of glial cells normally excluded from this region. Additionally, NM axons projected into inappropriate portions of NL in Z-DEVD-FMK treated embyros. We found that the presence of misrouted axons was associated with more severe NL disorganization. The effects of axonal caspase-3 inhibition on both NL morphogenesis and NM axon targeting suggest that these developmental processes are coordinated, likely through communication between axons and their targets.
Insights
Caspase-3 (cell death protease) is crucial for chick auditory brainstem development, guiding neuron pathfinding and nucleus formation. Inhibiting caspase-3 disrupts auditory pathway development and axon targeting.
Area of Science:
- Neuroscience
- Developmental Biology
- Cell Biology
Background:
- Caspase-3, a cysteine protease, is primarily known for its role in programmed cell death.
- Emerging evidence suggests caspase-3 also participates in cell differentiation, proliferation, and morphology.
- Its specific function in the development of the auditory brainstem remains largely unexplored.
Purpose of the Study:
- To investigate the role of caspase-3 in the embryogenesis of chick auditory brainstem nuclei.
- To elucidate the temporal and spatial expression patterns of caspase-3 during auditory pathway development.
- To determine the functional impact of caspase-3 inhibition on neuronal morphology and axon guidance.
Main Methods:
- Utilized immunofluorescence staining on chick embryos (E6-E13) to map cleaved caspase-3 expression.
- Administered a specific caspase-3 inhibitor (Z-DEVD-FMK) to block caspase-3 activity during critical developmental windows (E6-E9).
- Assessed the morphology of nucleus magnocellularis (NM) and nucleus laminaris (NL), and NM axonal targeting at E10 in treated and control embryos.
Main Results:
- Cleaved caspase-3 expression followed an ascending anatomical pathway within the developing auditory system, starting from the VIIIth nerve and progressing to NM and NL.
- Inhibition of caspase-3 led to disorganized NL lamination and abnormal glial cell infiltration in the surrounding neuropil.
- Blocking caspase-3 activity resulted in misrouted NM axons projecting to incorrect regions within the NL, with severity correlating to NL disorganization.
Conclusions:
- Caspase-3 plays a critical role in the normal development of chick auditory brainstem nuclei.
- The temporal and spatial expression of caspase-3 suggests its involvement in guiding axonal projections and organizing target nuclei.
- Axonal targeting and target nucleus morphogenesis appear to be coordinated processes, potentially mediated by caspase-3 signaling through axon-target interactions.
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