Role of KCC3 in Schwann cell development

KCC3 在雪旺细胞发育中的作用

• 批准号: 6790161
• 负责人: Nellie Eunjoo Byun
• 金额: $ 2.58万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6790161
• 关键词: Schwann cells; cell biology; cell migration; cell motility; cell proliferation; developmental neurobiology; genetic disorder; genetic regulation; genetically modified animals; laboratory mouse; membrane transport proteins; mental retardation; myelination; predoctoral investigator; protein structure function; sensory neuropathy

DESCRIPTION (provided by applicant): 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.

描述(申请人提供)：我们实验室已经培育出K+-氯-转运蛋白-3(KCC3)基因敲除小鼠，表现出严重的运动障碍。这种表型反映了人类KCC3基因突变患者的周围神经病变，这些患者患有一种名为Andermann综合征或ACCPN的神经疾病。两者均显示周围神经髓鞘异常，如髓鞘减少、脱髓鞘和纤维变性。虽然KCC3在出生后20天及以上的小鼠坐骨神经中未检测到，但初步的免疫染色结果表明，KCC3在发育早期的雪旺细胞(SC)小体中高表达，对应于SC迁移、增殖和髓鞘形成的时期。因此，我们假设KCC3在其中一个或多个过程中扮演关键角色。功能干细胞是至关重要的，因为正常的动作电位传导需要适当的髓鞘形成。这项提案的目标是确定KCC3在SC发展中的作用。虽然其生理作用尚不清楚，但KCC3介导K+和Cl-离子的电中和运动，可以调节细胞体积，并与细胞增殖有关。我们将首先确定KCC3在周围神经中的确切定位和表达模式。为了验证我们的假设，我们将比较野生型和KCC3-/-SCs的运动性、髓鞘形成能力、增殖和凋亡水平，以了解共转运体在SCs中的功能。这项研究还将揭示有关周围神经发育的新信息。