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Target-derived neurotrophic factors regulate the death of developing forebrain neurons after a change in their
R B Lotto1, P Asavaritikrai, L Vali
1Genes and Development Group, Department of Biomedical Sciences, University Medical School, Edinburgh EH8 9XD, United Kingdom.
Abstract:
Many neurons die as the normal brain develops. How this is regulated and whether the mechanism involves neurotrophic molecules from target cells are unknown. We found that cultured neurons from a key forebrain structure, the dorsal thalamus, develop a need for survival factors including brain-derived neurotrophic factor (BDNF) from their major target, the cerebral cortex, at the age at which they innervate it. Experiments in vivo have shown that rates of dorsal thalamic cell death are reduced by increasing cortical levels of BDNF and are increased in mutant mice lacking functional BDNF receptors or thalamocortical projections; these experiments have also shown that an increase in the rates of dorsal thalamic cell death can be achieved by blocking BDNF in the cortex. We suggest that the onset of a requirement for cortex-derived neurotrophic factors initiates a competitive mechanism regulating programmed cell death among dorsal thalamic neurons.
Insights
Brain development involves programmed cell death. Cortex-derived neurotrophic factors like brain-derived neurotrophic factor (BDNF) regulate dorsal thalamic neuron survival, initiating a competitive cell death mechanism.
Area of Science:
- Neuroscience
- Developmental Biology
Background:
- Programmed cell death is a normal process during brain development.
- The regulatory mechanisms and role of neurotrophic factors in this process are not fully understood.
Purpose of the Study:
- To investigate the role of neurotrophic factors, specifically brain-derived neurotrophic factor (BDNF), in regulating programmed cell death of dorsal thalamic neurons.
- To determine if target cells, like the cerebral cortex, provide essential survival factors for developing neurons.
Main Methods:
- In vitro culture of dorsal thalamic neurons.
- In vivo experiments in mice, including genetic manipulation (mutant mice lacking BDNF receptors) and experimental manipulation (blocking BDNF in the cortex).
Main Results:
- Dorsal thalamic neurons cultured in vitro develop a requirement for survival factors, including BDNF, from their target, the cerebral cortex.
- In vivo, increased cortical BDNF levels reduced dorsal thalamic cell death.
- Mutant mice lacking BDNF receptors or thalamocortical projections showed increased cell death.
- Blocking cortical BDNF increased dorsal thalamic cell death rates.
Conclusions:
- The onset of a requirement for cortex-derived neurotrophic factors, such as BDNF, initiates a competitive mechanism that regulates programmed cell death in dorsal thalamic neurons.
- This study highlights the critical role of target-derived neurotrophic factors in neuronal survival during brain development.