Center for Pediatric Genomics
Development of New RASopathy Mouse Models to Study Neurological Dysfunction

Development of New RASopathy Mouse Models to Study Neurological Dysfunction

Principle Investigators: Ronald Waclaw, Experimental Hematology & Cancer Biology, Cancer Biology

A photo of Ronald Waclaw.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 astrocytes. In addition, LZTR1 conditional mutants show increased expression of the astrocyte marker GFAP in multiple brain regions.

We are developing new mouse models to address the role of LZTR1 in astrocyte and white matter biology. We are generating a mouse model for the dominant LZTR1 mutation Y193H and developing an allelic series to test how LZTR1 gene dosage impacts astrocyte and white matter development. We also are analyzing behavioral changes to see if these mice exhibit neurocognitive dysfunction. In addition, we are testing if the MAPK pathway is the key contributor to the LZTR1 cKO astrocyte phenotype by using a cre inducible dominant negative MEK1 mutation transgenic mouse (dnMEK) to lower MAPK signaling in telencephalon specific LZTR1 cKO with Foxg1cre/+. We are identifying a core LZTR1 dependent gene signature in the white matter by comparing transcriptomes of LZTR1 dominant mice LZTR1 Y193H/+ and LZTR1 deficient mice (Lztr1loxP/loxP;Foxg1cre/+). These studies will identify the specific roles of LZTR1 during astrocyte development and provide new mouse models key to understanding LZTR1 dominant mutations in RASopathy biology.

Projects Funded by CpG

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