Abstract
SummaryEngagement of neural stem/progenitor cells (NSPCs) into proper neuronal differentiation requires the spatiotemporally regulated generation of metabolites. Purines are essential building blocks for many signaling molecules. Enzymes that catalyze de novo purine synthesis are assembled as a huge multienzyme complex called “purinosome.” However, there is no evidence of the formation or physiological function of the purinosome in the brain. Here, we showed that a signal transduction ATPases with numerous domains (STAND) protein, NACHT and WD repeat domain-containing 1 (Nwd1), interacted with Paics, a purine-synthesizing enzyme, to regulate purinosome assembly in NSPCs. Altered Nwd1 expression affected purinosome formation and induced the mitotic exit and premature differentiation of NSPCs, repressing neuronal migration and periventricular heterotopia. Overexpression/knockdown of Paics or Fgams, other purinosome enzymes, in the developing brain resulted in a phenocopy of Nwd1 defects. These findings indicate that strict regulation of purinosome assembly/disassembly is crucial for maintaining NSPCs and corticogenesis.
Highlights
The spatiotemporal differentiation of neural stem/progenitor cells (NSPCs) into immature neurons and neuronal migration are necessary for the proper development of the central nervous system (CNS)
Enzymes that catalyze de novo purine synthesis are assembled as a huge multienzyme complex called ‘‘purinosome.’’ there is no evidence of the formation or physiological function of the purinosome in the brain
We showed that a signal transduction ATPases with numerous domains (STAND) protein, NACHT and WD repeat domain-containing 1 (Nwd1), interacted with Paics, a purine-synthesizing enzyme, to regulate purinosome assembly in NSPCs
Summary
The spatiotemporal differentiation of neural stem/progenitor cells (NSPCs) into immature neurons and neuronal migration are necessary for the proper development of the central nervous system (CNS). Compounds containing a pyrimidine ring fused with an imidazole ring, are found in all living species and include the nucleobases adenine and guanine (Traut, 1994). Apart from their critical function as the building blocks of DNA (deoxyadenosine and deoxyguanosine) and RNA (adenosine and guanosine), purines work as components of essential biomolecules and as a source of second messenger molecules (cyclic AMP and cyclic GMP), cofactors coenzyme A and nicotinamide adenine dinucleotide (NADH), cellular energy substrate ATP, and GTP, which is essential for the signal transduction of a large number of G-proteins. Purinergic signaling is essential for NSPC maintenance and neuronal migration in the neocortical SVZ (Lin et al, 2007; Liu et al, 2008)
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