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Nervous system defects of AnkyrinB (-/-) mice suggest functional overlap between the cell adhesion molecule L1 and
P Scotland1, D Zhou, H Benveniste
1Howard Hughes Medical Institute, Departments of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Abstract:
The L1 CAM family of cell adhesion molecules and the ankyrin family of spectrin-binding proteins are candidates to collaborate in transcellular complexes used in diverse contexts in nervous systems of vertebrates and invertebrates. This report presents evidence for functional coupling between L1 and 440-kD ankyrinB in premyelinated axons in the mouse nervous system. L1 and 440-kD ankyrinB are colocalized in premyelinated axon tracts in the developing nervous system and are both down-regulated after myelination. AnkyrinB (-/-) mice exhibit a phenotype similar to, but more severe, than L1 (-/-) mice and share features of human patients with L1 mutations. AnkyrinB (-/-) mice exhibit hypoplasia of the corpus callosum and pyramidal tracts, dilated ventricles, and extensive degeneration of the optic nerve, and they die by postnatal day 21. AnkyrinB (-/-) mice have reduced L1 in premyelinated axons of long fiber tracts, including the corpus callosum, fimbria, and internal capsule in the brain, and pyramidal tracts and lateral columns of the spinal cord. L1 was evident in the optic nerve at postnatal day 1 but disappeared by postnatal day 7 in mutant mice while NCAM was unchanged. Optic nerve axons of ankyrinB (-/-) mice become dilated with diameters up to eightfold greater than normal, and they degenerated by day 20. These findings provide the first evidence for a role of ankyrinB in the nervous system and support an interaction between 440-kD ankyrinB and L1 that is essential for maintenance of premyelinated axons in vivo.
Insights
Cell adhesion molecule L1 and ankyrinB protein interaction is crucial for maintaining premyelinated axons in the mouse nervous system. Loss of ankyrinB causes severe axon defects and early death, highlighting its essential role in neural development.
Area of Science:
- Neuroscience
- Cell Biology
- Developmental Biology
Background:
- Cell adhesion molecules like L1 and spectrin-binding proteins like ankyrin are implicated in neural complex formation.
- Functional coupling between L1 and ankyrinB in premyelinated axons is hypothesized.
Purpose of the Study:
- To investigate the functional coupling between L1 and 440-kD ankyrinB in the mouse nervous system.
- To elucidate the role of ankyrinB in the maintenance of premyelinated axons.
Main Methods:
- Colocalization studies of L1 and 440-kD ankyrinB in developing mouse nervous systems.
- Phenotypic analysis of ankyrinB knockout mice (ankyrinB-/-) compared to L1 knockout mice (L1-/-).
- Assessment of L1 expression and axon morphology in optic nerves of ankyrinB-/- mice.
Main Results:
- L1 and 440-kD ankyrinB are colocalized in premyelinated axon tracts and down-regulated after myelination.
- AnkyrinB-/- mice display a more severe phenotype than L1-/- mice, including hypoplasia of major brain tracts, dilated ventricles, optic nerve degeneration, and early death.
- AnkyrinB deficiency leads to reduced L1 in axons and severe optic nerve axon dilation and degeneration.
Conclusions:
- This study provides the first evidence for ankyrinB's role in the nervous system.
- A critical interaction between 440-kD ankyrinB and L1 is essential for in vivo maintenance of premyelinated axons.
- AnkyrinB deficiency results in severe neural developmental defects mirroring aspects of human L1 mutation disorders.