Retrograde Signaling from Progranulin to Sort1 Counteracts Synapse Elimination in the Developing Cerebellum
Retrograde Signaling from Progranulin to Sort1 Counteracts Synapse Elimination in the Developing Cerebellum
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DOI：
10.1016/j.neuron.2018.01.018
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发表时间：
2018-02-21
期刊：
影响因子：
16.2
通讯作者：
Kano, Masanobu
中科院分区：
文献类型：
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作者：
Uesaka, Naofumi;Abe, Manabu;Kano, Masanobu
消除发育早期形成的多余突触和加强必要的连接对于形成功能性神经回路至关重要。新生儿小脑浦肯野细胞（PCs）受多条强度相似的攀爬纤维（CFs）支配。在出生后的发育过程中，单个CF得到加强，而其他CF在每个PC中被消除。人们对其基本机制，特别是加强单一中央财政基金的机制了解甚少。在这里，我们报告了与额颞叶痴呆发病机制有关的多功能生长因子前蛋白，加强了CF突触输入的发展，并抵消了它们在出生后11至16天的消除。来源于PCs的前颗粒蛋白逆行作用于其在CFs上的假定受体Sort1。这种作用独立于信号蛋白3A，另一种逆行信号分子抵消CF突触消除。我们认为，蛋白前蛋白- sort1信号通路加强并维持发育中的CF输入，并可能有助于选择在突触消除后存活下来的单个“赢家”CF。
Elimination of redundant synapses formed early in development and strengthening of necessary connections are crucial for shaping functional neural circuits. Purkinje cells (PCs) in the neonatal cerebellum are innervated by multiple climbing fibers (CFs) with similar strengths. A single CF is strengthened whereas the other CFs are eliminated in each PC during postnatal development. The underlying mechanisms, particularly for the strengthening of single CFs, are poorly understood. Here we report that progranulin, amulti-functional growth factor implicated in the pathogenesis of frontotemporal dementia, strengthens developing CF synaptic inputs and counteracts their elimination from postnatal day 11 to 16. Progranulin derived from PCs acts retrogradely onto its putative receptor Sort1 on CFs. This effect is independent of semaphorin 3A, another retrograde signaling molecule that counteracts CF synapse elimination. We propose that progranulin-Sort1 signaling strengthens and maintains developing CF inputs, and may contribute to selection of single "winner'' CFs that survive synapse elimination.