Cho, Jun-HungPatel, BhaumikBonala, SantoshManne, SasikanthZhou, YanVadrevu, Surya K.Patel, JalpaPeronaci, MarcoGhouse, ShanawazHenske, ElizabethRoegiers, FabriceGiannikou, KrinioKwiatkowski, DavidMansouri, HosseinMarkiewski, Maciej M.White, BrandonKarbowniczek, Magdalena2018-01-182017Cho, J., B. Patel, S. Bonala, S. Manne, Y. Zhou, S. K. Vadrevu, J. Patel, et al. 2017. “Notch transactivates Rheb to maintain the multipotency of TSC-null cells.” Nature Communications 8 (1): 1848. doi:10.1038/s41467-017-01845-1. http://dx.doi.org/10.1038/s41467-017-01845-1.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34651796Differentiation abnormalities are a hallmark of tuberous sclerosis complex (TSC) manifestations; however, the genesis of these abnormalities remains unclear. Here we report on mechanisms controlling the multi-lineage, early neuronal progenitor and neural stem-like cell characteristics of lymphangioleiomyomatosis (LAM) and angiomyolipoma cells. These mechanisms include the activation of a previously unreported Rheb-Notch-Rheb regulatory loop, in which the cyclic binding of Notch1 to the Notch-responsive elements (NREs) on the Rheb promoter is a key event. This binding induces the transactivation of Rheb. The identified NRE2 and NRE3 on the Rheb promoter are important to Notch-dependent promoter activity. Notch cooperates with Rheb to block cell differentiation via similar mechanisms in mouse models of TSC. Cell-specific loss of Tsc1 within nestin-expressing cells in adult mice leads to the formation of kidney cysts, renal intraepithelial neoplasia, and invasive papillary renal carcinoma.en-USJournal Article2018-01-1810.1038/s41467-017-01845-1