| First Author | Huang CY | Year | 2017 |
| Journal | J Neurosci | Volume | 37 |
| Issue | 47 | Pages | 11311-11322 |
| PubMed ID | 29038240 | Mgi Jnum | J:254073 |
| Mgi Id | MGI:6101323 | Doi | 10.1523/JNEUROSCI.2112-17.2017 |
| Citation | Huang CY, et al. (2017) alphaII Spectrin Forms a Periodic Cytoskeleton at the Axon Initial Segment and Is Required for Nervous System Function. J Neurosci 37(47):11311-11322 |
| abstractText | Spectrins form a submembranous cytoskeleton proposed to confer strength and flexibility to neurons and to participate in ion channel clustering at axon initial segments (AIS) and nodes of Ranvier. Neuronal spectrin cytoskeletons consist of diverse beta subunits and alphaII spectrin. Although alphaII spectrin is found in neurons in both axonal and somatodendritic domains, using proteomics, biochemistry, and superresolution microscopy, we show that alphaII and betaIV spectrin interact and form a periodic AIS cytoskeleton. To determine the role of spectrins in the nervous system, we generated Sptan1(f/f) mice for deletion of CNS alphaII spectrin. We analyzed alphaII spectrin-deficient mice of both sexes and found that loss of alphaII spectrin causes profound reductions in all beta spectrins. alphaII spectrin-deficient mice die before 1 month of age and have disrupted AIS and many other neurological impairments including seizures, disrupted cortical lamination, and widespread neurodegeneration. These results demonstrate the importance of the spectrin cytoskeleton both at the AIS and throughout the nervous system.SIGNIFICANCE STATEMENT Spectrin cytoskeletons play diverse roles in neurons, including assembly of excitable domains such as the axon initial segment (AIS) and nodes of Ranvier. However, the molecular composition and structure of these cytoskeletons remain poorly understood. Here, we show that alphaII spectrin partners with betaIV spectrin to form a periodic cytoskeleton at the AIS. Using a new alphaII spectrin conditional knock-out mouse, we show that alphaII spectrin is required for AIS assembly, neuronal excitability, cortical lamination, and to protect against neurodegeneration. These results demonstrate the broad importance of spectrin cytoskeletons for nervous system function and development and have important implications for nervous system injuries and diseases because disruption of the spectrin cytoskeleton is a common molecular pathology. |
