title: Deficiency of the housekeeping gene hypoxanthine-guanine phosphoribosyltransferase (HPRT) dysregulates neurogenesis.
abstract: Neuronal transcription factors play vital roles in the specification and development of neurons, including dopaminergic (DA) neurons. Mutations in the gene encoding the purine biosynthetic enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) cause the resulting intractable and largely untreatable neurological impairment of Lesch-Nyhan disease (LND). The disorder is associated with a defect in basal ganglia DA pathways. The mechanisms connecting the purine metabolic defect and the central nervous system (CNS) phenotype are poorly understood but have been presumed to reflect a developmental defect of DA neurons. We have examined the effect of HPRT deficiency on the differentiation of neurons in the well-established human (NT2) embryonic carcinoma neurogenesis model. We have used a retrovirus expressing a small hairpin RNA (shRNA) to knock down HPRT gene expression and have examined the expression of a number of transcription factors essential for neuronal differentiation and marker genes involved in DA biosynthetic pathway. HPRT-deficient NT2 cells demonstrate aberrant expression of several transcription factors and DA markers. Although differentiated HPRT-deficient neurons also demonstrate a striking deficit in neurite outgrowth during differentiation, resulting neurons demonstrate wild-type electrophysiological properties. These results represent direct experimental evidence for aberrant neurogenesis in HPRT deficiency and suggest developmental roles for other housekeeping genes in neurodevelopmental disease.
authors: Department of Pediatrics, Center for Molecular Genetics, University of California, San Diego School of Medicine, La Jolla, California 92093-0634, USA.
authors: Ghiabe-Henri
authors: GH
authors: Guibinga
authors: Stephen
authors: S
authors: Hsu
authors: Theodore
authors: T
authors: Friedmann
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D004594:Electrophysiology; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000378:metabolism
chemical_list: D007041:Hypoxanthine Phosphoribosyltransferase