The KH-type splicing regulatory protein (KHSRP) is an RNA-binding protein linked to decay of AU-rich element containing mRNAs. We have previously shown that KHSRP destabilizes the mRNA encoding the growth-associated protein GAP-43 and decreases neurite growth in cultured embryonic neurons. In contrast, loss of KHSRP stabilizes Gap43 mRNA and increases neurite growth. Here, we have tested functions of neural KHSRP in vivo. We find upregulation of 1460 mRNAs in the neocortex of adult Khsrp-/- mice, of which 527 bind to KHSRP with high specificity. These KHSRP targets are involved in pathways for neuronal morphology, axon guidance, neurotransmission and long-term memory. Neocortical neurons show increased axon growth and dendritic spine density in Khsrp-/- mice. Analyses of neuronal cultures from embryonic Khsrp-/- mice point to a neuron-intrinsic alteration in axonal and dendritic growth and elevations in KHSRP-target mRNAs, including subcellularly localized mRNAs. Hippocampus and infralimbic cortex of Khsrp-/- mice show presynaptic elevations in neurotransmission. The Khsrp-/- mice have significant deficits in both trace conditioning and attention set-shifting tasks compared Khsrp+/+ mice, indicating impaired prefrontal- and hippocampal-dependent memory consolidation with loss of KHSRP. Overall, our results indicate that prenatal deletion of KHSRP impairs neuronal development resulting in alterations in neuronal morphology and function by changing post-transcriptional control of neuronal gene expression.

中文翻译：

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KHSRP的丢失增加了神经元的生长和突触传递，并通过RNA稳定改变了记忆巩固

KH型剪接调节蛋白（KHSRP）是一种RNA结合蛋白，与含有AU的富元素的mRNA衰变有关。先前我们已经表明，KHSRP使编码与生长相关的蛋白质GAP-43的mRNA不稳定，并减少了培养的胚胎神经元中神经突的生长。相反，KHSRP的丢失可稳定Gap43 mRNA并增加神经突的生长。在这里，我们已经在体内测试了神经KHSRP的功能。我们发现成年Khsrp-/-小鼠新皮层中的1460个mRNA上调，其中527个与KHSRP具有高特异性结合。这些KHSRP靶标涉及神经元形态，轴突引导，神经传递和长期记忆的途径。在Khsrp-/-小鼠中，新皮质神经元显示轴突生长和树突棘密度增加。来自胚胎Khsrp-/-小鼠的神经元培养物的分析表明，神经元内在性的轴突和树突状生长以及KHSRP靶标mRNA（包括亚细胞定位mRNA）的升高。Khsrp-/-小鼠的海马和下肢皮质在神经传递中显示突触前升高。与Khsrp + / +小鼠相比，Khsrp-/-小鼠在痕量条件和注意力转移任务上均具有明显的缺陷，表明前额叶和海马依赖性记忆整合受损，且KHSRP丢失。总的来说，我们的结果表明，通过改变转录后对神经元基因表达的控制，KHSRP的产前缺失会损害神经元发育，从而导致神经元形态和功能的改变。包括亚细胞定位的mRNA。Khsrp-/-小鼠的海马和下肢皮质在神经传递中显示突触前升高。与Khsrp + / +小鼠相比，Khsrp-/-小鼠在痕量条件和注意力转移任务上均具有明显的缺陷，表明前额叶和海马依赖性记忆整合受损，且KHSRP丢失。总的来说，我们的结果表明，通过改变转录后对神经元基因表达的控制，KHSRP的产前缺失会损害神经元发育，从而导致神经元形态和功能的改变。包括亚细胞定位的mRNA。Khsrp-/-小鼠的海马和下肢皮质在神经传递中显示突触前升高。与Khsrp + / +小鼠相比，Khsrp-/-小鼠在痕量条件和注意力转移任务上均具有明显的缺陷，表明前额叶和海马依赖性记忆整合受损，且KHSRP丢失。总的来说，我们的结果表明，通过改变转录后对神经元基因表达的控制，KHSRP的产前缺失会损害神经元发育，从而导致神经元形态和功能的改变。提示前额叶和海马依赖性记忆整合受损，并伴有KHSRP丢失。总的来说，我们的结果表明，通过改变转录后对神经元基因表达的控制，KHSRP的产前缺失会损害神经元发育，从而导致神经元形态和功能的改变。提示前额叶和海马依赖性记忆整合受损，并伴有KHSRP丢失。总的来说，我们的结果表明，通过改变转录后对神经元基因表达的控制，KHSRP的产前缺失会损害神经元发育，从而导致神经元形态和功能的改变。