PTEN Regulates Dendritic Arborization by Decreasing Microtubule Polymerization Rate
PTEN Regulates Dendritic Arborization by Decreasing Microtubule Polymerization Rate
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DOI：
10.1523/jneurosci.1835-21.2022
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发表时间：
2022-03-09
影响因子：
5.3
通讯作者：
Luikart, Bryan W.
中科院分区：
文献类型：
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作者：
Getz, Stephanie A.;Tariq, Kamran;Luikart, Bryan W.
磷酸酶和张力蛋白同源物（PTEN）是磷脂酰肌醇-3-激酶（PI 3 K）/Akt/雷帕霉素机制靶点（mTOR）途径的主要负调节剂。在患有大头畸形和自闭症谱系障碍（ASD）的一部分患者中已经发现了PTEN的功能缺失突变。神经元中的PTEN缺失导致体肥大、异常迁移、树突过度生长、棘密度增加和神经元回路的过度活跃。这些神经元过度生长表型存在于Pten敲除（KO）和自闭症相关点突变的重建中。Pten缺陷神经元中树突过度生长的机制尚不清楚。在这项研究中，我们研究了如何使用逆转录病毒感染和转染策略来操纵PTEN表达和标记正末端MT结合蛋白，末端结合蛋白3（EB 3）的Pten损失影响微管（MT）在两种性别的动态。我们发现Pten KO神经元与野生型（WT）神经元相比，随着时间的推移会产生更多的新过程。我们还发现在Pten KO树枝状生长锥中MT聚合速率增加。将MT聚合速率降低至WT水平足以在体外和体内减少Pten KO神经元中的树突过度生长。最后，我们发现通过抑制MT聚合来拯救树突过度生长足以改善Pten KO小鼠在空间记忆任务中的表现。两者合计，我们的数据表明，一个因素潜在的PTEN损失依赖性树突状细胞过度生长是增加MT聚合。这开启了用低剂量抑制剂靶向MT聚合和mTOR的交叉方法的可能性，以在与神经元PTEN功能丧失相关的病理中实现具有最小副作用的治疗增益。
Phosphatase and tensin homolog (PTEN) is a major negative regulator of the phosphatidylinositol-3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway. Loss-of-function mutations in PTEN have been found in a subset of patients with macrocephaly and autism spectrum disorder (ASD). PTEN loss in neurons leads to somal hypertrophy, aberrant migration, dendritic overgrowth, increased spine density, and hyperactivity of neuronal circuits. These neuronal overgrowth phenotypes are present on Pten knock-out (KO) and reconstitution with autism-associated point mutations. The mechanism underlying dendritic overgrowth in Pten deficient neurons is unclear. In this study, we examined how Pten loss impacts microtubule (MT) dynamics in both sexes using retroviral infection and transfection strategies to manipulate PTEN expression and tag the plus-end MT binding protein, end-binding protein 3 (EB3). We found Pten KO neurons sprout more new processes over time compared with wild-type (WT) neurons. We also found an increase in MT polymerization rate in Pten KO dendritic growth cones. Reducing MT polymerization rate to the WT level was sufficient to reduce dendritic overgrowth in Pten KO neurons in vitro and in vivo. Finally, we found that rescue of dendritic overgrowth via inhibition of MT polymerization was sufficient to improve the performance of Pten KO mice in a spatial memory task. Taken together, our data suggests that one factor underlying PTEN loss dependent dendritic overgrowth is increased MT polymerization. This opens the possibility for an intersectional approach targeting MT polymerization and mTOR with low doses of inhibitors to achieve therapeutic gains with minimal side effects in pathologies associated with loss of neuronal PTEN function.