Dr. Timothy Gomez and colleagues recently had an article, “RHOA signaling defects result in impaired axon guidance in iPSC-derived neurons from patients with tuberous sclerosis complex,” published in Nature Communications.
Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder characterized by cortical tubers and neural network connectivity defects. Patients with TSC show aberrant wiring of neuronal connections formed during development which may contribute to symptoms of TSC, such as intellectual disabilities, autism, and epilepsy.
Yet models examining the molecular basis for axonal guidance defects in developing human neurons have not been developed.
In their article, the Gomez lab generated human induced pluripotent stem cell (hiPSC) lines from a patient with TSC and genetically engineered counterparts and isogenic controls. They showed that control neurons responded to canonical guidance cues as predicted. Conversely, neurons with heterozygous loss of TSC2 exhibit reduced responses to several repulsive cues and defective axon guidance. While TSC2 is a known key negative regulator of MTOR-dependent protein synthesis, we find that TSC2 signaled through MTOR-independent RHOA in growth cones.
Their results suggest that neural network connectivity defects in patients with TSC may result from defects in RHOA-mediated regulation of cytoskeletal dynamics during neuronal development.
For Full paper, click here: Catlett, T.S., Onesto, M.M., McCann, A.J. et al. RHOA signaling defects result in impaired axon guidance in iPSC-derived neurons from patients with tuberous sclerosis complex. Nat Commun 12, 2589 (2021). https://doi.org/10.1038/s41467-021-22770-4