The KH-type splicing regulatory protein (KHSRP) is an RNA-binding protein linked to decay of mRNAs with AU-rich elements. KHSRP was previously shown to destabilize Gap43 mRNA and decrease neurite growth in cultured embryonic neurons. Here, we have tested functions of KHSRP in vivo. We find upregulation of 1460 mRNAs in 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. Khsrp^−/− mice show increased axon growth and dendritic spine density in vivo. Neuronal cultures from Khsrp^−/− mice show increased axon and dendrite growth and elevated KHSRP-target mRNAs, including subcellularly localized mRNAs. Furthermore, neuron-specific knockout of Khsrp confirms these are from neuron-intrinsic roles of KHSRP. Consistent with this, neurons in the hippocampus and infralimbic cortex of Khsrp^−/− mice show elevations in frequency of miniature excitatory postsynaptic currents. The Khsrp^−/− mice have deficits in trace conditioning and attention set-shifting tasks compared Khsrp^+/+ mice, indicating impaired prefrontal- and hippocampal-dependent memory consolidation with loss of KHSRP. Overall, these results indicate that deletion of KHSRP impairs neuronal development resulting in alterations in neuronal morphology and function by changing post-transcriptional control of neuronal gene expression.

KH 型剪接调节蛋白 (KHSRP) 是一种 RNA 结合蛋白，与富含 AU 元件的 mRNA 的衰变有关。 KHSRP 先前已被证明会破坏Gap43 mRNA 的稳定性并减少培养的胚胎神经元中神经突的生长。在这里，我们测试了 KHSRP 的体内功能。我们发现成年Khsrp ^−/−小鼠新皮质中 1460 个 mRNA 上调，其中 527 个与 KHSRP 高度特异性结合。这些 KHSRP 靶点涉及神经元形态、轴突引导、神经传递和长期记忆的通路。 Khsrp ^-/−小鼠体内轴突生长和树突棘密度增加。 Khsrp ^-/−小鼠的神经元培养物显示轴突和树突生长增加，KHSRP 靶标 mRNA 升高，包括亚细胞定位 mRNA。此外， Khsrp的神经元特异性敲除证实了这些来自 KHSRP 的神经元固有作用。与此一致的是， Khsrp ^−/−小鼠海马体和边缘下皮层的神经元显示出微型兴奋性突触后电流的频率升高。与Khsrp ^+/+小鼠相比， Khsrp ^−/−小鼠在痕迹调节和注意力转移任务方面存在缺陷，表明前额叶和海马依赖的记忆巩固受损，并且 KHSRP 丢失。总的来说，这些结果表明，KHSRP 的缺失会损害神经元发育，通过改变神经元基因表达的转录后控制，导致神经元形态和功能的改变。