Functional Significance of L1 Retrotransposition

描述（由申请人提供）：个体表现出明显的行为反应差异。即使在基因相似的近亲繁殖小鼠品系中，个体对行为任务和压力源的反应也各不相同。这种行为差异的背后是神经元层面的巨大多样性。可能有多达10,000种不同类型的神经元，它们在结构，分子组成（例如，不同离子通道组合的表达）以及与其他神经元的连接方面可能有所不同。这种异质性仅产生于约30,000个基因，并决定了神经元回路的运作方式；然而，这种神经元多样性的来源仍不清楚。DNA重组被认为是这种多样性的一个来源。LINE-1 （Long Interspersed Nuclear Elements 1，“L1”）逆转录转座子是基因组中的活性元件，可以在生殖细胞和神经前体细胞中调动。当被动员时，L1反转录转座子可能改变基因表达，潜在地支持神经元异质性和个体差异；然而，L1逆转位的功能作用在很大程度上仍不确定。关注胚胎和成人L1的插入，本提案将解决L1逆转录导致行为和神经元表型个体差异的假设。目的1将确定环境经验如何调节L1活性。目标2将开发转基因和药理学方法来减弱L1活性。最后，目的3将研究减弱L1逆转录如何影响对显著环境经验的行为反应和神经元表型的反应。

DESCRIPTION (provided by applicant): Individuals demonstrate marked differences in behavioral responses. Even within genetically similar inbred mouse strains, individuals vary in their responses to behavioral tasks and stressors. Underlying this behavioral variation is tremendous diversity at the neuronal level. There may be as many as 10,000 different types of neurons, which can differ in structure, molecular make-up (e.g., expression of different combinations of ion channels), and connections to other neurons. This heterogeneity arises from only ~30,000 genes and determines how neuronal circuits operate; however, the source of such neuronal diversity remains unclear. DNA recombination has been proposed as one source of such diversity. LINE-1 (Long Interspersed Nuclear Elements 1; "L1") retrotransposons are active elements in the genome that can mobilize in germ cells and neuronal precursor cells. When mobilized, L1 retrotransposons may alter gene expression, potentially supporting neuronal heterogeneity and individual variations; however, the functional role of L1 retrotransposition remains largely undetermined. Focusing on both embryonic and adult L1 insertions, this proposal will address the hypothesis that L1 retrotransposition contributes to individual differences in behavioral and neuronal phenotypes. Aim 1 will determine how environmental experience may modulate L1 activity. Aim 2 will develop transgenic and pharmacological approaches to attenuate L1 activity. And finally, Aim 3 will investigate how attenuating L1 retrotransposition influences behavioral responses and neuronal phenotypes in response to salient environmental experiences.