Pinceau Organization in the Cerebellum Requires Distinct Functions of Neurofascin in Purkinje and Basket Neurons during Postnatal Development
Pinceau Organization in the Cerebellum Requires Distinct Functions of Neurofascin in Purkinje and Basket Neurons during Postnatal Development
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DOI：
10.1523/jneurosci.5602-11.2012
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发表时间：
2012-04-04
影响因子：
5.3
通讯作者：
Bhat, Manzoor A.
中科院分区：
文献类型：
--
作者：
Buttermore, Elizabeth D.;Piochon, Claire;Bhat, Manzoor A.
篮状轴突侧支与浦肯野索马/轴突起始段（AIS）区域形成特化结构，即枕索，其对于正常小脑功能至关重要。小脑发育过程中针索如何组织的机制细节知之甚少。细胞骨架衔接蛋白锚蛋白G（AnkG）的缺失导致细胞粘附分子神经成束蛋白（Nfasc）在浦肯野AIS的错误定位和针座组织的异常。成年浦肯野神经元中Nfasc的缺失导致浦肯野AIS和针形形态的缓慢解体。在这里，我们使用小鼠条件性基因敲除技术，以显示Nfasc的选择性损失，特别是在浦肯野神经元在早期发展，防止成熟的AIS，并导致浦肯野神经元自发活动和pinceau解体的损失。浦肯野神经元和篮状神经元中Nfasc的缺失引起异常篮状轴突侧支分支和靶向浦肯野索马/AIS，导致广泛的针索紊乱、浦肯野神经元变性和严重共济失调。我们的研究表明，浦肯野Nfasc是所需的AIS成熟和维持稳定的接触之间的篮状轴突终末和浦肯野AIS在pinceau组织，而篮状神经元Nfasc与浦肯野Nfasc的组合是所需的适当的篮状轴突侧支生长和浦肯野索马/AIS的目标。因此，小脑针索组织需要协调机制，涉及特定的Nfasc功能在浦肯野和篮子神经元。
Basket axon collaterals synapse onto the Purkinje soma/axon initial segment (AIS) area to form specialized structures, the pinceau, which are critical for normal cerebellar function. Mechanistic details of how the pinceau become organized during cerebellar development are poorly understood. Loss of cytoskeletal adaptor protein Ankyrin G (AnkG) results in mislocalization of the cell adhesion molecule Neurofascin (Nfasc) at the Purkinje AIS and abnormal organization of the pinceau. Loss of Nfasc in adult Purkinje neurons leads to slow disorganization of the Purkinje AIS and pinceau morphology. Here, we used mouse conditional knock-out techniques to show that selective loss of Nfasc, specifically in Purkinje neurons during early development, prevented maturation of the AIS and resulted in loss of Purkinje neuron spontaneous activity and pinceau disorganization. Loss of Nfasc in both Purkinje and basket neurons caused abnormal basket axon collateral branching and targeting to Purkinje soma/AIS, leading to extensive pinceau disorganization, Purkinje neuron degeneration, and severe ataxia. Our studies reveal that the Purkinje Nfasc is required for AIS maturation and for maintaining stable contacts between basket axon terminals and the Purkinje AIS during pinceau organization, while the basket neuron Nfasc in combination with Purkinje Nfasc is required for proper basket axon collateral outgrowth and targeting to Purkinje soma/AIS. Thus, cerebellar pinceau organization requires coordinated mechanisms involving specific Nfasc functions in both Purkinje and basket neurons.