Hypoxanthine impairs morphogenesis and enhances proliferation of a neuroblastoma model of Lesch Nyhan syndrome.
Extracellular purines have essential roles in neuronal development; hence, disruptions in their metabolism as reported in Lesch Nyhan syndrome (LNS) could result in developmental abnormalities. The deficiency of hypoxanthine-guanine phosphoribosyl transferase (HGPRT) in LNS leads to increased hypoxanthine and uric acid production. We have reported that HGPRT-deficient B103-4C neuroblastoma, a neuronal model of LNS, proliferated less and differentiated more than their HGPRT-positive B103 counterparts. Here, we sought to determine whether differences in proliferation and differentiation would occur when these cells were cultured in the presence of hypoxanthine or in a hypoxanthine-/serum-free chemically defined media (NBMN2). In media with 1% serum, hypoxanthine (50 microM) significantly increased the proliferation of both cell lines with a greater effect on B103-4C cells. In 1% serum media, hypoxanthine increased differentiation of B103 but decreased B103-4C differentiation. In NBMN2, B103 proliferated far more than B103-4C, but both cell types differentiated to the same extent. These results are interpreted to suggest that elevated levels of central nervous system (CNS) hypoxanthine as reported in LNS may affect neuronal development, and to implicate hypoxanthine and abnormal neuronal development as causative factors in the etiology of LNS.
Purine NeuroScience Laboratory, Chemical Pathology, Guy's, King's and St. Thomas' School of Medicine, King's College London, Guy's Campus, London SE1 9RT, United Kingdom.
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Stacey
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Connolly
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003470:Culture Media / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects; D019271:Hypoxanthine / Q000494:pharmacology*; D007926:Lesch-Nyhan Syndrome / Q000209:etiology* / Q000378:metabolism; D009447:Neuroblastoma; D009474:Neurons / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D014407:Tumor Cells, Cultured
D003470:Culture Media; D019271:Hypoxanthine