Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival
Authors: Iwona Gumper
Alejo Efeyan
Steven Chang
Roberto Zoncu
Rachel L Wolfson
Harriet Snitkin
David D Sabatini
David M Sabatini
Oktay Kirak
Journal: Nature (2013)
Discipline: Multidisciplinary
Keywords: mTORC1 pathway; RagA-D GTPases; neonates; hypoglycaemia; autophagy
Affiliations: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.

Abstract:  The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates organismal growth in response to many environmental cues, including nutrients and growth factors. Cell-based studies showed that mTORC1 senses amino acids through the RagA-D family of GTPases (also known as RRAGA, B, C and D), but their importance in mammalian physiology is unknown. Here we generate knock-in mice that express a constitutively active form of RagA (RagA(GTP)) from its endogenous promoter. RagA(GTP/GTP) mice develop normally, but fail to survive postnatal day 1. When delivered by Caesarean section, fasted RagA(GTP/GTP) neonates die almost twice as rapidly as wild-type littermates. Within an hour of birth, wild-type neonates strongly inhibit mTORC1, which coincides with profound hypoglycaemia and a decrease in plasma amino-acid concentrations. In contrast, mTORC1 inhibition does not occur in RagA(GTP/GTP) neonates, despite identical reductions in blood nutrient amounts. With prolonged fasting, wild-type neonates recover their plasma glucose concentrations, but RagA(GTP/GTP) mice remain hypoglycaemic until death, despite using glycogen at a faster rate. The glucose homeostasis defect correlates with the inability of fasted RagA(GTP/GTP) neonates to trigger autophagy and produce amino acids for de novo glucose production. Because profound hypoglycaemia does not inhibit mTORC1 in RagA(GTP/GTP) neonates, we considered the possibility that the Rag pathway signals glucose as well as amino-acid sufficiency to mTORC1. Indeed, mTORC1 is resistant to glucose deprivation in RagA(GTP/GTP) fibroblasts, and glucose, like amino acids, controls its recruitment to the lysosomal surface, the site of mTORC1 activation. Thus, the Rag GTPases signal glucose and amino-acid concentrations to mTORC1, and have an unexpectedly key role in neonates in autophagy induction and thus nutrient homeostasis and viability. 

Retracted: No

PubPeer comments:
 Supplemental Fig. 1e u2013 possible duplication. Could the authors check? ![file] , 
 My name is Alejo Efeyan, first author of this paper and currently a PI at the CNIO in Madrid. I have re-analyzed the original pictures and, indeed, a representative image of the same RagAGTP GTP embryo was shown twice, instead of the mistakenly replaced image of a second RagAGTP + embryo, most likely while preparing this Supplementary figure with representative images of E13.5 embryos. This issue most likely went unnoticed because all embryos, regardless of genotype, look very similar to the naked eye. I am attaching here a corrected version of the supplementary panel, containing now the correct image of the second RagAGTP + embryo that should have been included in the original figure. The other 5 images already present, including that of the other RagAGTP + representative embryo and original images of two RagAGTP GTP embryos, remain unchanged. Of note, all pictures were obtained from the same litter of embryos and were taken on October 6th 2010. It is important to note that neither this very minor mistake nor its correction affect the validity of the data, its interpretation, conclusions drawn, or any other aspect of the published paper. Nevertheless, we will contact the Nature Editorial Office to let them know about this mistake and its correction.![file] , 
 Are the authors still planning to issue a Corrigendum to correct this duplication? It s been two years since this discussion, but I cannot find any update on the official paper s landing page. ,