Neurofibromatosis-1 regulates mTOR-mediated astrocyte growth and glioma formation in a TSC/Rheb-independent manner

Abstract

Converging evidence from the analysis of human brain tumors and genetically engineered mice has revealed that the mammalian target of rapamycin (mTOR) pathway is a central regulator of glial and glioma cell growth. In this regard, mutational inactivation of neurofibromatosis-1 (NF1), tuberous sclerosis complex (TSC), and PTEN genes is associated with glioma formation, such that pharmacologic inhibition of mTOR signaling results in attenuated tumor growth. This shared dependence on mTOR suggests that PTEN and NF1 (neurofibromin) glial growth regulation requires TSC/Rheb (Ras homolog enriched in brain) control of mTOR function. In this report, we use a combination of genetic silencing in vitro and conditional mouse transgenesis approaches in vivo to demonstrate that neurofibromin regulates astrocyte cell growth and glioma formation in a TSC/Rheb-independent fashion. First, we show that Nf1 or Pten inactivation, but not Tsc1 loss or Rheb overexpression, increases astrocyte cell growth in vitro. Second, Nf1 -deficient increased mTOR signaling and astrocyte hyperproliferation is unaffected by Rheb shRNA silencing. Third, conditional Tsc1 inactivation or Rheb overexpression in glial progenitors of Nf1 +/− mice does not lead to glioma formation. Collectively, these findings establish TSC/Rheb-independent mechanisms for mTOR-dependent glial cell growth control and gliomagenesis relevant to the design of therapies for individuals with glioma.

Physical interaction between neurofibromin and serotonin 5-HT 6 receptor promotes receptor constitutive activity

“…Another pathway engaged by 5-HT 6 receptor that might contribute to cognitive impairment in NF1 patients is the mTOR pathway. Loss of neurofibromin Ras-GAP activity in NF1 leads to aberrant mTOR activation, which is essential for NF1-associated malignancies (34). Moreover, nonphysiological mTOR activation has been involved in cognitive deficits observed in several neurodevelopmental disorders (35).…”

Maternal diet–induced microRNAs and mTOR underlie β cell dysfunction in offspring

“…Rheb mice were generated by a knockin strategy using a backbone knockin ROSA-26-tetracycline-regulated transcriptional activator (tTA) as previously described (56). Protein quantifications.…”

Deconvoluting mTOR biology

“…Compared with other tissues, 143-145 the biological effects of mTOR activation resulting from Pten loss, Nf1 loss, Tsc1 loss and RHEB overexpression in astrocytes are distinct 28 ( Fig. 6B).…”

“…27 Loss of neurofibromin expression in astrocytes or neural stem cells in the brain results in increased RAS activation, and leads to high levels of activated AKT and MEK signaling, which converge on the mTOR complex to regulate cell growth. [27][28][29] In this respect, inhibition of mTOR hyperactivation using the macrolide rapamycin inhibits the growth of malignant peripheral nerve sheath tumors and optic gliomas in genetically engineered mice. [30][31][32] These exciting preclinical observations have leveraged the design and execution of new clinical trials Figure 1.…”