Pitpnc1a Regulates Zebrafish Sleep and Wake Behavior through Modulation of Insulin-like Growth Factor Signaling.
Pitpnc1a Regulates Zebrafish Sleep and Wake Behavior through Modulation of Insulin-like Growth Factor Signaling.
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DOI：
10.1016/j.celrep.2018.07.012
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发表时间：
2018-08-07
期刊：
影响因子：
8.8
通讯作者：
Rihel J
中科院分区：
文献类型：
--
作者：
Ashlin TG;Blunsom NJ;Ghosh M;Cockcroft S;Rihel J
磷脂酰肌醇转移蛋白（PITP）家族的脂质转运蛋白决定了磷酸肌醇的区隔，特定的磷酸肌醇在信号级联、膜交通、离子通道调节和肌动蛋白动力学中起着至关重要的作用。尽管pitp在大脑中丰富，但其在体内神经元信号通路中的生理功能仍不明确。我们描述了CRISPR/ cas9产生的斑马鱼脑特异性，保守的II类PITP成员pitpnc1a突变体。斑马鱼pitpnc1a突变体是健康的，但在昼夜循环中表现出广泛的异常神经元活动和增加的觉醒。Pitpnc1a的缺失增加了大脑中的胰岛素样生长因子（IGF）信号，抑制IGF通路足以挽救Pitpnc1a突变体的神经元和行为亢进。我们提出表达pitpnc1a的神经元通过改变作用于下游唤醒回路的神经调节IGF来改变行为。斑马鱼有两个同源物，一个大脑丰富，CRISPR/Cas9产生的pitpnc1a突变体在整个昼夜周期中都异常活跃，胰岛素样生长因子信号在pitpnc1a突变体中失调。阻断IGF信号通路可缓解pitpnc1a突变体的行为和神经元亢进。Ashlin等人发现，缺乏脑富集脂质转运体pitpnc1a的CRISPR/Cas9斑马鱼突变体具有胰岛素样生长因子（IGF）信号失调和行为亢进。这项工作表明，Pitpnc1a通常通过抑制IGF来调节神经元兴奋性的设定点。
The lipid transporters of the phosphatidylinositol transfer protein (PITP) family dictate phosphoinositide compartmentalization, and specific phosphoinositides play crucial roles in signaling cascades, membrane traffic, ion channel regulation, and actin dynamics. Although PITPs are enriched in the brain, their physiological functions in neuronal signaling pathways in vivo remain ill defined. We describe a CRISPR/Cas9-generated zebrafish mutant in a brain-specific, conserved class II PITP member, pitpnc1a. Zebrafish pitpnc1a mutants are healthy but display widespread aberrant neuronal activity and increased wakefulness across the day-night cycle. The loss of Pitpnc1a increases insulin-like growth factor (IGF) signaling in the brain, and inhibition of IGF pathways is sufficient to rescue both neuronal and behavioral hyperactivity in pitpnc1a mutants. We propose that Pitpnc1a-expressing neurons alter behavior via modification of neuro-modulatory IGF that acts on downstream wake-promoting circuits. Zebrafish have two orthologs, one brain enriched, of the lipid transporter PITPNC1 CRISPR/Cas9-generated pitpnc1a mutants are hyperactive across the day-night cycle Insulin-like growth factor signaling is dysregulated in pitpnc1a mutants Blocking IGF signaling rescues pitpnc1a mutant behavioral and neuronal hyperactivity Ashlin et al. find that CRISPR/Cas9 zebrafish mutants that lack the brain-enriched lipid transporter Pitpnc1a have dysregulated insulin-like growth factor (IGF) signaling and behavioral hyperactivity. This work suggests that Pitpnc1a normally regulates the set point of neuronal excitability by dampening IGF.
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