Control of axonal growth and regeneration of sensory neurons by the p110delta PI 3-kinase.
Control of axonal growth and regeneration of sensory neurons by the p110delta PI 3-kinase.
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DOI：
10.1371/journal.pone.0000869
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发表时间：
2007-09-11
期刊：
影响因子：
3.7
通讯作者：
Vanhaesebroeck B
中科院分区：
文献类型：
--
作者：
Eickholt BJ;Ahmed AI;Davies M;Papakonstanti EA;Pearce W;Starkey ML;Bilancio A;Need AC;Smith AJ;Hall SM;Hamers FP;Giese KP;Bradbury EJ;Vanhaesebroeck B
磷脂酰肌醇3 - 激酶（PI3K）的8种不同催化亚型在神经系统中的表达及功能尚不明确。大多数PI3K具有广泛的组织分布，而之前已表明与酪氨酸激酶相关的p110δ亚型在白细胞中富集。在此我们报道p110δ在神经系统中也高度表达。小鼠体内p110δ失活并不影响神经元的总体发育，但会导致背根神经节神经元更易出现生长锥塌陷以及轴突延伸减少。p110δ活性缺失还会抑制成年小鼠外周神经损伤后的轴突再生，并损害运动功能的恢复。p110δ失活导致通过Akt蛋白激酶的神经元信号传导减少，以及小GTP酶RhoA活性增加。对RhoA的下游效应物ROCK进行药理抑制，可恢复p110δ失活的神经元的轴突延伸缺陷，这表明RhoA在神经元中p110δ信号传导中起关键作用。我们的数据确定p110δ是发育和再生神经系统中有效轴突伸长的重要信号传导组分。
The expression and function of the 8 distinct catalytic isoforms of PI 3-kinase (PI3K) in the nervous system are unknown. Whereas most PI3Ks have a broad tissue distribution, the tyrosine kinase-linked p110δ isoform has previously been shown to be enriched in leukocytes. Here we report that p110δ is also highly expressed in the nervous system. Inactivation of p110δ in mice did not affect gross neuronal development but led to an increased vulnerability of dorsal root ganglia neurons to exhibit growth cone collapse and decreases in axonal extension. Loss of p110δ activity also dampened axonal regeneration following peripheral nerve injury in adult mice and impaired functional recovery of locomotion. p110δ inactivation resulted in reduced neuronal signaling through the Akt protein kinase, and increased activity of the small GTPase RhoA. Pharmacological inhibition of ROCK, a downstream effector of RhoA, restored axonal extension defects in neurons with inactive p110δ, suggesting a key role of RhoA in p110δ signaling in neurons. Our data identify p110δ as an important signaling component for efficient axonal elongation in the developing and regenerating nervous system.
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