D-cysteine is an endogenous regulator of neural progenitor cell dynamics in the mammalian brain

Evan R. Semenza, Maged M. Harraz, Efrat Abramson, Adarsha P. Malla, Chirag Vasavda, Moataz M. Gadalla, Michael D. Kornberg, Solomon H. Snyder, Robin Roychaudhuri

Research output: Contribution to journalArticlepeer-review


D-amino acids are increasingly recognized as important signaling molecules in the mammalian central nervous system. However, the D-stereoisomer of the amino acid with the fastest spontaneous racemization ratein vitro in vitro, cysteine, has not been examined in mammals. Using chiral high-performance liquid chromatography and a stereospecific luciferase assay, we identify endogenous D-cysteine in the mammalian brain. We identify serine racemase (SR), which generates the N-methyl-D-aspartate (NMDA) glutamate receptor coagonist D-serine, as a candidate biosynthetic enzyme for D-cysteine. D-cysteine is enriched more than 20-fold in the embryonic mouse brain compared with the adult brain. D-cysteine reduces the proliferation of cultured mouse embryonic neural progenitor cells (NPCs) by ∼50%, effects not shared with D-serine or L-cysteine. The antiproliferative effect of D-cysteine is mediated by the transcription factors FoxO1 and FoxO3a. The selective influence of D-cysteine on NPC proliferation is reflected in overgrowth and aberrant lamination of the cerebral cortex in neonatal SR knockout mice. Finally, we perform an unbiased screen for D-cysteine–binding proteins in NPCs by immunoprecipitation with a D-cysteine–specific antibody followed by mass spectrometry. This approach identifies myristoylated alanine-rich C-kinase substrate (MARCKS) as a putative D-cysteine–binding protein. Together, these results establish endogenous mammalian D-cysteine and implicate it as a physiologic regulator of NPC homeostasis in the developing brain.

Original languageEnglish (US)
Article numbere2110610118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number39
StatePublished - Sep 28 2021


  • Cortical development
  • D-cysteine
  • FoxO
  • Neural progenitor cell
  • Serine racemase

ASJC Scopus subject areas

  • General


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