Our laboratory has generated K+-Cl-contransporter-3 (KCC3) knockout mice, which exhibit severe locomotor deficits. This phenotype mirrors the peripheral neuropathy in patients with mutations in the human KCC3 gene who suffer from a neurological disorder termed Andermann syndrome, or ACCPN. Both show myelination abnormalities in peripheral nerves, e.g. hypomyelination, demyelination, and fiber degeneration. Although KCC3 is undetectable in sciatic nerve of mice postnatal 20 days and older, preliminary immunostaining results show that KCC3 is highly expressed in Schwann cell (SC) bodies during early development, which corresponds to the period of SC migration, proliferation, and myelination. Thus we hypothesize that KCC3 lays a critical role in one or more of these processes. Functional SCs are crucial since proper myelination is necessary for normal action potential conduction. The goal of this proposal is to define the role of KCC3 in SC development. Although its physiological role is unknown, KCC3 mediates the electroneutral movement of K+ and Cl- ions, can regulate cell volume, and is associated with cell proliferation. We will first determine the exact localization and expression pattern of KCC3 in peripheral nerves. Then to test our hypothesis, we will compare motility, myelination ability, and proliferation and apoptosis levels between wild type and KCC3-/-SCs in order to understand cotransporter function in SCs. This study will also reveal new information on peripheral nerve development.
| Byun, Nellie; Delpire, Eric (2007) Axonal and periaxonal swelling precede peripheral neurodegeneration in KCC3 knockout mice. Neurobiol Dis 28:39-51 |
