Impact of LZTR1 Mutations on Oligodendrocyte Development and Function

摘要 BTB Kelch家族成员基因LZTR 1是RAS/MAPK信号传导的上游调节因子，在 癌症和RAS综合征。Lztr 1是一种不寻常的RASopathy基因， 常染色体显性和隐性努南综合征的例子。研究细胞影响的小鼠模型 Lztr 1缺陷的研究由于种系突变和心脏缺陷的致死性而具有挑战性。因此，我们认为， Lztr 1在中枢神经系统中的作用仍然是未知的。我们从一个新的 所产生的端脑特异性Lztr 1条件突变体显示， 白色区含有髓鞘少突胶质细胞（OL）。此外，Lztr 1条件突变体 显示OL发育的阶段特异性标志物的表达缺陷。单细胞RNA测序揭示 Lztr 1在OL发育的祖细胞和成熟阶段均有表达。在这里，我们建议开发 新的小鼠模型来解决Lztr 1在OL生物学中的作用。在第一个目标中，我们将测试 通过在OL早期和晚期产生细胞类型特异性条件突变体在OL发育中的作用 发展我们还将建立显性Lztr 1突变Y193 H的小鼠模型，并开发一种新的基因治疗方法。 等位基因系列，以测试Lztr 1基因剂量如何影响OL发育。在第二个目标中，我们将测试是否错误- Lztr 1的表达通过降低RAS/MAPK信号传导影响OL谱系。我们还将测试是否表达 Lztr 1改善Nf 1 RAS病小鼠模型中的异常RAS/MAPK活化和OL表型。最后， 我们将通过比较转录组， Lztr 1和Nf 1小鼠模型。这些研究将确定Lztr 1在不同阶段OL中的具体作用 开发并提供新的小鼠模型，这是理解Lztr 1信号传导机制和RAS病的关键 生物学

Abstract The BTB Kelch family member gene LZTR1 is an upstream regulator of RAS/MAPK signaling and is mutated in both cancers and RASopathy syndromes. Lztr1 is an unusual RASopathy gene that is observed in both autosomal dominant and recessive examples of Noonan Syndrome. Mouse models to study the cellular impact of Lztr1 deficiency have been challenging due to the lethality of germline mutants and cardiac defects. Therefore, the role of Lztr1 in the central nervous system remains largely unknown. Our preliminary data from a newly generated telencephalon specific Lztr1 conditional mutant revealed enriched activation of the MAPK pathway in the white matter region containing the myelinating oligodendrocytes (OLs). In addition, Lztr1 conditional mutants show defects in the expression of stage specific markers of OL development. Single cell RNA sequencing reveal that Lztr1 is expressed in both progenitor and mature stages of OL development. Here we propose to develop new mouse models to address the role of Lztr1 in OL biology. In the first aim, we will test the requirement of Lztr1 during OL development by generating cell type specific conditional mutants at early and late stages of OL development. We will also generate a mouse model for the dominant Lztr1 mutation Y193H and develop an allelic series to test how Lztr1 gene dosage impacts OLs development. In the second aim, we will test if mis- expression of Lztr1 impacts the OL lineage by lowering RAS/MAPK signaling. We will also test if expression of Lztr1 improves aberrant RAS/MAPK activation and OL phenotypes in Nf1 RASopathy mouse models. Finally, we will identify a core RASopathy gene expression signature in the OL lineage by comparing transcriptomes of Lztr1 and Nf1 mouse models. These studies will identify the specific roles of Lztr1 during distinct stages OL development and provide new mouse models key to understanding Lztr1 signaling mechanism and RASopathy biology.