Rheb Conditional Knockout mouse models

Rheb, ortholog of human RHEB, encodes a farnesylated small GTPase that anchors to lysosomal membranes through its carboxy-terminal CAAX motif and, in the GTP-bound state, binds the mTOR kinase domain directly to relieve an inhibitory conformation and switch on mTORC1 phosphorylation of S6K1 and 4E-BP1. Its intrinsic hydrolysis rate is low, so pathway control is exerted almost entirely by the TSC1, TSC2 and TBC1D7 complex acting as a GTPase-activating protein, which explains why tuberous sclerosis mutations produce constitutive RHEB-GTP and rapamycin-sensitive overgrowth, and why activating substitutions such as Y35N behave as oncogenic drivers. Germline deletion is embryonic lethal, making conditional nulls the practical design for organ growth studies, while Cre-inducible Y35N knockins test sufficiency for mTORC1 activation without disturbing amino acid input through the Rag GTPases. The paralog Rhebl1 has restricted expression and does not broadly compensate, so single-locus phenotypes are generally interpretable.

Tissue restricted knockout of Rheb keeps wild type function everywhere else. Breeding is often more robust, and the setup mirrors patient biology where mutations arise in a subset of cells.