Acute dietary methionine restriction triggers cell cycle arrest and reversible growth defects in the neocortex

Methionine is indispensable for cell proliferation, stem cell maintenance, and epigenetic regulation, three processes that are central to embryonic development. Here, we assessed the consequences of short-term dietary methionine restriction (MR) on mouse embryonic organ growth. In comparison with growth of the liver and heart which was unaffected, MR for 5 days led to a severe reduction in neuronal production and neocortex growth. Progenitor cohort labeling revealed a time-dependent sensitivity to MR and cell cycle analysis indicated that progenitors are stalled in S/G2 phases following MR. Unexpectedly, neuronal production was completely rescued at birth when switching the dam back to control diet, uncovering a mechanism of catch-up growth. We used imaging mass cytometry to probe metabolic and epigenetic markers in neural progenitors following MR and during catch-up growth. Altogether, our data uncover a reversible state of quiescence in S/G2 which is metabolically distinct from G0 quiescence and associated with efficient catch-up growth of the neocortex.