Impact of LZTR1 Mutations on Oligodendrocyte Development and Function

摘要 BTB Kelch家族成员基因LZTR1是RAS/MAPK信号的上游调节因子，并在 癌症和类风湿综合征。LZTR1是一种罕见的RAS病基因，在两种疾病中均可观察到 常染色体显性和隐性Noonan综合征病例。研究细胞影响的小鼠模型 由于生殖系突变和心脏缺陷的致命性，LZTR1缺乏症的发生一直是具有挑战性的。因此， LZTR1在中枢神经系统中的作用在很大程度上仍不清楚。我们的初步数据来自一项新的 端脑特异的LZTR1条件突变体显示MAPK通路在 白质区域含有髓鞘少突胶质细胞(OLs)。此外，LZTR1条件突变体 在OL发育的阶段特异性标志物的表达上存在缺陷。单细胞RNA测序揭示 LZTR1在OL发育的祖细胞和成熟阶段都有表达。在这里，我们建议开发 解决LZTR1在OL生物学中的作用的新小鼠模型。在第一个目标中，我们将测试 LZTR1通过在OL的早期和晚期产生细胞类型特异性的条件突变来促进OL的发育 发展。我们还将为显性LZTR1突变Y193H建立小鼠模型，并开发一种 等位基因序列，以测试LZTR1基因剂量如何影响OL的发育。在第二个目标中，我们将测试是否错误- LZTR1的表达通过降低RAS/MAPK信号影响OL谱系。我们还将测试是否表达了 LZTR1改善Nf1 RAS病小鼠模型中RAS/MAPK的异常激活和OL表型。最后， 我们将通过比较以下基因的转录本来确定OL谱系中的核心类风湿关节炎基因表达特征 LZTR1和NF1小鼠模型。这些研究将确定LZTR1在不同的OL阶段中的具体作用 开发和提供了解LZTR1信号机制和类风湿性关节炎的新小鼠模型 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.