Loss of arginase I results in increased proliferation of neural stem cells.
Loss of arginase I (AI) results in a metabolic disorder characterized by growth retardation, increased mental impairment and spasticity, and potentially fatal hyperammonemia. This syndrome plus a growing body of evidence supports a role for arginase and arginine metabolites in normal neuronal development and function. Here we report our initial observations of the effects of AI loss on proliferation and differentiation of neural stem cells (NSCs) isolated from the germinal zones of embryonic and newborn AI knockout (KO) mice compared with heterozygous (HET) and wild-type (WT) control animals. By using both short and long-term proliferation assays (3 and 10 days, respectively), we found a 1.5-2-fold increase in the number of KO cells compared with WT. FACS analysis showed an increase in KO cells in the synthesis phase of the cell cycle vs. WT cells. After NSC differentiation, AI-deficient cells expressed beta-tubulin, SMI81 (SNAP25), glial fibrillary acidic protein, and CNPase, which are markers consistent with neurons, astrocytes, and oligodendrocytes. Many KO cells exhibited a more mature morphology and expressed mature neuronal markers that were decreased or not present in HET or WT cells. Limited, comparative expression array and quantitative RT-PCR analysis identified differences in the levels of several mRNAs encoding structural, signaling, and arginine metabolism proteins between KO and WT cells. The consequence of these changes may contribute to the differential phenotypes of KO vs. WT cells. It appears that AI may play an important and unanticipated role in growth and development of NSCs.
Becker-Catania
Sara G
SG
Edward Hines Jr. Veterans Administration Hospital, Hines, Illinois, USA.
Gregory
Teresa L
TL
Yang
Yawei
Y
Gau
Chia-Ling
CL
de Vellis
Jean
J
Cederbaum
Stephen D
SD
Iyer
Ramaswamy K
RK
D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005434:Flow Cytometry / Q000379:methods; D015870:Gene Expression / Q000502:physiology; D020162:Hyperargininemia; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012249:Rhombencephalon / Q000166:cytology / Q000196:embryology; D013234:Stem Cells / Q000502:physiology*
D009419:Nerve Tissue Proteins