Seminar

Nutrient sensing and mTOR: from neonatal metabolism to adult physiology

Alejo Efeyan, PhD

The mechanistic target of rapamycin complex 1 (mTORC1) drives cellular anabolic processes when both systemic and local nutrients are plentiful. The circuitry of cellular nutrient signaling started to be deciphered seven years ago with the identification of the Rag GTPases, direct interactors and activators of mTORC1 upon nutrient sufficiency. The relevance of this signaling pathway for mammalian physiology is still broadly incomplete, and we have employed mouse genetics to understand it. Genetically engineered mice with constitutive cellular nutrient signaling die at birth due to a metabolic crisis secondary to impairment in autophagy. We have now rescued neonatal lethality to study the physiology of deregulated nutrient sensing in adult mice. Adult mice with constitutive Rag activity show metabolic and behavioral perturbations and premature death. In parallel, we have found that deregulated Rag activity has profound consequences for normal B cell development and functions, and ac tivating point mutations in the Rag family are frequently found in human B cell lymphomas.