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Published on: May 12, 2015
Nervous-tissue-specific elimination of microtubule-actin crosslinking factor 1a results in multiple developmental
Dmitry Goryunov1, Cui-Zhen He, Chyuan-Sheng Lin
1Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians and Surgeons, NY, NY 10032, USA.
Abstract:
The microtubule-actin crosslinking factor 1 (MACF1) is a ubiquitous cytoskeletal linker protein with multiple spliced isoforms expressed in different tissues. The MACF1a isoform contains microtubule and actin-binding regions and is expressed at high levels in the nervous system. Macf1-/- mice are early embryonic lethal and hence the role of MACF1 in the nervous system could not be determined. We have specifically knocked out MACF1a in the developing mouse nervous system using Cre/loxP technology. Mutant mice died within 24-36h after birth of apparent respiratory distress. Their brains displayed a disorganized cerebral cortex with a mixed layer structure, heterotopia in the pyramidal layer of the hippocampus, disorganized thalamocortical and corticofugal fibers, and aplastic anterior and hippocampal commissures. Embryonic neurons showed a defect in traversing the cortical plate. Our data suggest a critical role for MACF1 in neuronal migration that is dependent on its ability to interact with both microfilaments and microtubules.
Insights
Microtubule-actin crosslinking factor 1a (MACF1a) is crucial for nervous system development. Its absence in mice disrupts neuronal migration, leading to severe brain disorganization and early death.
Area of Science:
- Cell Biology
- Neuroscience
- Developmental Biology
Background:
- Microtubule-actin crosslinking factor 1 (MACF1) is a cytoskeletal linker protein with various isoforms.
- The MACF1a isoform, abundant in the nervous system, binds both microtubules and actin filaments.
- Previous studies on MACF1's role in the nervous system were limited due to early embryonic lethality of Macf1-/- mice.
Purpose of the Study:
- To investigate the specific role of the MACF1a isoform in the developing mouse nervous system.
- To elucidate the function of MACF1a in neuronal development and migration.
Main Methods:
- Generation of MACF1a-specific knockout mice using Cre/loxP technology.
- Analysis of brain structure and neuronal migration in mutant mice.
- Examination of embryonic neuron behavior in vitro.
Main Results:
- MACF1a knockout mice exhibited respiratory distress and died within 24-36 hours post-birth.
- Mutant brains showed severe cortical disorganization, hippocampal heterotopia, and fiber tract defects.
- Embryonic neurons from knockout mice displayed impaired migration through the cortical plate.
Conclusions:
- MACF1a plays a critical role in neuronal migration during nervous system development.
- The function of MACF1a in neuronal migration depends on its dual interaction with microfilaments and microtubules.
- Specific knockout of MACF1a provides insights into its essential functions in the developing brain.
