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Abnormal cerebellar development and foliation in BDNF-/- mice reveals a role for neurotrophins in CNS patterning
P M Schwartz1, P R Borghesani, R L Levy
1Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
Abstract:
While target-derived neurotrophins are required for the survival of developing neurons in the PNS, the functions of neurotrophins in the CNS are unclear. Mice with a targeted gene deletion of brain-derived neurotrophic factor (BDNF) exhibit a wide-based gait. Consistent with this behavioral evidence of cerebellar dysfunction, there is increased death of granule cells, stunted growth of Purkinje cell dendrites, impaired formation of horizontal layers, and defects in the rostral-caudal foliation pattern. These abnormalities are accompanied by decreased Trk activation in granule and Purkinje cells of mutant animals, indicating that both cell types are direct targets for BDNF. These data suggest that BDNF acts as an anterograde or an autocrine-paracrine factor to regulate survival and morphologic differentiation of developing CNS neurons, and thereby affects neural patterning.
Insights
Brain-derived neurotrophic factor (BDNF) is crucial for central nervous system (CNS) neuron survival and development. BDNF deficiency in mice leads to cerebellar dysfunction, affecting neuron growth and neural patterning.
Area of Science:
- Neuroscience
- Developmental Biology
- Molecular Biology
Background:
- Neurotrophins are vital for peripheral nervous system (PNS) neuron survival.
- The specific roles of neurotrophins within the central nervous system (CNS) remain largely undefined.
Purpose of the Study:
- To investigate the function of brain-derived neurotrophic factor (BDNF) in the developing CNS.
- To elucidate the cellular and molecular mechanisms underlying BDNF's role in neural development and patterning.
Main Methods:
- Utilized a targeted gene deletion approach in mice to study BDNF's function.
- Analyzed behavioral phenotypes, cerebellar histology, and Trk receptor activation in mutant and wild-type animals.
Main Results:
- Mice lacking BDNF displayed cerebellar dysfunction, evidenced by a wide-based gait.
- Significant abnormalities were observed, including increased granule cell death, impaired Purkinje cell dendritic growth, and defects in cerebellar foliation.
- Reduced Trk activation in granule and Purkinje cells confirmed these cell types as direct BDNF targets.
Conclusions:
- BDNF is essential for the survival and morphologic differentiation of developing CNS neurons.
- BDNF functions in an anterograde or autocrine-paracrine manner to regulate neural development and patterning within the CNS.