Spatiotemporal Regulation ofDe Novoand Salvage Purine Synthesis during Brain Development

Abstract

The levels of purines, essential molecules to sustain eukaryotic cell homeostasis, are regulated by the coordination of thede novoand salvage synthesis pathways. In the embryonic central nervous system (CNS), thede novopathway is considered crucial to meet the requirements for the active proliferation of neural stem/progenitor cells (NSPCs). However, how these two pathways are balanced or separately used during CNS development remains poorly understood. In this study, we showed a dynamic shift in pathway utilization, with greater reliance on thede novopathway during embryonic stages and on the salvage pathway in postnatal–adult mouse brain. The pharmacological effects of various purine synthesis inhibitorsin vitroand the expression profile of purine synthesis enzymes indicated that NSPCs in the embryonic cerebrum mainly use thede novopathway. Simultaneously, NSPCs in the cerebellum require both thede novoand the salvage pathways.In vivoadministration ofde novoinhibitors resulted in severe hypoplasia of the forebrain cortical region, indicating a gradient of purine demand along the anteroposterior axis of the embryonic brain, with cortical areas of the dorsal forebrain having higher purine requirements than ventral or posterior areas such as the striatum and thalamus. This histologic defect of the neocortex was accompanied by strong downregulation of the mechanistic target of rapamycin complex 1 (mTORC1)/ribosomal protein S6 kinase (S6K)/S6 signaling cascade, a crucial pathway for cell metabolism, growth, and survival. These findings indicate the importance of the spatiotemporal regulation of both purine pathways for mTORC1 signaling and proper brain development.

Babies, bugs and brains: How the early microbiome associates with infant brain and behavior development

“…(2022), where the amplitudes of brain responses to rhythms were larger in the left hemisphere [40]. Perhaps of most interest in the results are the associations between BEAT_FL and pathways related to bacterial pentose phosphate pathways, which lead to the formation of metabolites with neuroactive properties that can modulate the brain, such as SCFA, and the nucleosides/nucleotides salvage, which is necessary to maintain the levels of nucleotides in times or rapid growth and development, among other pathways [26,27,[88][89][90].…”

“…The other top associations with BEAT_FL were pathways related to nucleosides/nucleotides degradation or salvage (S2 Table ). Nucleosides/nucleotides are essential nutrients during times of rapid growth and development, such as during infants' early life [88][89][90]. The increase of these pathways may be explained as an increase in the nucleotide/ nucleoside metabolism to degrade the metabolites from the food source and salvage it for own usage, instead of de novo synthesis of the compound.…”

The microcephaly protein WDR62 regulates cellular purine metabolism through the HSP70/HSP90 chaperone machinery

“…It remains to be determined whether the purine metabolic defects observed in our in vitro experiments would be replicated by WDR62 mutations in patients, and which tissues or cell types would exhibit the most pronounced defects. Purines play a role in supporting the rapid growth, division, and differentiation of neural progenitors during neurogenesis by providing nucleotides, energy, and purinergic signalling, all of which are all crucial for proper brain development [70–73]. In line with this, the loss of purine metabolic enzymes, including HPRT, disrupts neurogenesis, resulting in microcephaly, cell cycle defects, ciliopathies, and abnormalities in proliferation and neural progenitor fate decisions, mirroring the loss of WDR62 [29].…”