Advisory Committee Chair
Robert A Kesterson
Advisory Committee Members
David M Bedwell
Andra R Frost
Ludwine M Messiaen
Lalita R Shevde-Samant
Document Type
Dissertation
Date of Award
2018
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Loss of NF1 in different developmental and cellular contexts leads to unique physiological outcomes due to loss of neurofibromin function, including embryonic lethality, sporadic cancers, and the genetic disorder NF1. Neurofibromin acts as a tumor suppressor by modulation of RAS signaling, with other functions of this multi-domain protein being less clear. Even within the monogenic disorder of NF1, the clinical heterogeneity and mutational spectrum are immense, revealing the complexity underlying this disorder. There is a huge urgency and need for NF1 therapeutic treatments, and the same urgency to develop in vivo models to better understand NF1 that can be utilized in preclinical studies. Two novel mouse models harboring mutations found in individuals with NF1 were created and characterized, including nonsense Nf1Arg681* and missense Nf1Gly848Arg. The two different human NF1 mutations examined have unique consequences and effects on neurofibromin expression and phenotype, recapitulating unique aspects of NF1. Both of these models provide valuable systems for evaluating new mutation-guided therapies. Additionally, two novel Nf1 conditional knockout mouse models were generated to develop more rapid methods to assess neurofibromin function, a macrophage- and dendritic cell-specific Nf1 knockout model (Csf1riCre; Nf14F/4F) and a tamoxifen-inducible systemic Nf1 knockout model (CAGGCre-ERTM; Nf14F/4F). Csf1riCre; Nf14F/4F mice displayed no overt tumor or myeloproliferative phenotype. CAGGCre-ERTM; Nf14F/4F mice displayed an acute, lethal phenotype, characterized by decreased body fat, metabolic dysfunction, and no survival beyond 11 days following tamoxifen induction. This reveals that Nf1 is essential for the viability and metabolic function of the adult mouse. The systemic Nf1 knockout model provides an acute phenotype that offers a rapid method of assessment of neurofibromin function, and when paired with genetically engineered mouse models harboring human NF1 mutations can serve as an alternative model system in preclinical studies for mutation-guided therapies.
Recommended Citation
Turner, Ashley Nicole, "Novel insights into neurofibromin function and human neurofibromatosis type 1 mutations using genetically engineered mouse models" (2018). All ETDs from UAB. 3183.
https://digitalcommons.library.uab.edu/etd-collection/3183