Martin et al took advantage of the unique attributes of the iPSC model system as they aimed to contribute toward a deeper understanding of neurocognitive consequences observed in TSC. They explored molecular effects of a private TSC1 gene pathogenic variant and the effects and limitations of sirolimus (rapamycin) in patient-specific skin fibroblast-derived iPSCs.8 The patient affected by TSC carried a truncating nonsense variant in TSC1 exon 15 (1746C>T, Arg509X). Using CRISPR/Cas9 technique, the investigators generated a null TSC1-iPSCs as well as “corrected” wild-type (Corr-WT) of the heterozygous TSC1-Het iPSCs with TSC1 (1746C>T, Arg509X) variant. The isogenic iPSCs (Het, Null, and Corr-WT) were then differentiated into neural progenitor cells (NPCs). As would be expected, compared to Corr-WT, the TSC1-Het and Null NPCs were larger in size and they proliferated faster in a dose-dependent manner, a finding consistent with the activation of mTORC1 complex reflected in downstream increase in expression levels of the phosphoribosomal protein S6. The TSC-Het and Null also showed increased number and length of neurites. Signaling through mTORC1 and mTORC2 complexes was shown to be important for the development and morphology of dendrites and axonal outgrowth.2 Administration of rapamycin reduced cell size but not the proliferation rate, and it did not affect neurite length or number. This finding is supported by prior experimental studies in a Tsc1 knockout mice, which has shown that dendritic patterning is modulated in an mTOR-independent manner through mitogen-activated protein kinases (MEK) that regulate phosphorylation of extracellular signal-regulated kinases (ERK).2,9 The MEK-ERK was shown to be aberrantly activated in SEGAs,8 and a similar activation and elevation of phosphorylated ERK (pERK) was noticed in the current study. Interestingly, pretreatment with rapamycin, while blocking mTORC1 activation, led to a significant increase in pERK1/2 in TSC-Het and Null and it was abolished by an application of MEK inhibitor trametinib. An MEK-related pathway and interaction important for the dynamic process of neuronal synaptic plasticity is mitogen-activated protein kinase–interacting kinase (MNK). The MNK phosphorylates and thus regulates the binding of eukaryotic translation initiation factor 4E (eIF4E) to its target proteins, such as fragile X mental retardation protein (FMRP) and cytoplasmic fragile X protein-interacting protein 1 (CYFIP1). The FMRP/CYFIP1 complex then regulates FMRP targets and messenger RNAs involved in cytoskeletal regulation and growth.10 In the study by Martin et al, the baseline phosphorylation status of eIE4A was comparable among Corr-WT, TSC-Het, and Null, but rapamycin application led to PI3K-dependent activation of MNK-eIE4A signaling. These findings, at least in part, may explain the sustained cellular proliferation and neurite length and number despite rapamycin treatment. Transcriptome comparative profiling of the TSC-Het and Null versus Corr-WT uncovered 107 differentially expressed genes shared between TSC-Het and Null, and 29 of 107 genes showed gene dose-dependent up- or downregulation. Among the dysregulated genes were the zinc-finger family of DNA-binding transcription factors, transcriptional regulators, and notably PCDH19, PCDH10, ANXA1, CNTN6, and HLA-B with a known association with epilepsy, ASD, and ID.