Hypoxanthine deregulates genes involved in early neuronal development. Implications in Lesch-Nyhan disease pathogenesis.
Neurological manifestations in Lesch-Nyhan disease (LND) are attributed to the effect of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency on the nervous system development. HPRT deficiency causes the excretion of increased amounts of hypoxanthine into the extracellular medium and we hypothesized that HPRT deficiency related to hypoxanthine excess may then lead, directly or indirectly, to transcriptional aberrations in a variety of genes essential for the function and development of striatal progenitor cells. We have examined the effect of hypoxanthine excess on the differentiation of neurons in the well-established human NTERA-2 cl.D1 (NT2/D1) embryonic carcinoma neurogenesis model. NT2/D1 cells differentiate along neuroectodermal lineages after exposure to retinoic acid (RA). Hypoxanthine effects on RA-differentiation were examined by the changes on the expression of various transcription factor genes essential to neuronal differentiation and by the changes in tyrosine hydroxylase (TH), dopamine, adenosine and serotonin receptors (DRD, ADORA, HTR). We report that hypoxanthine excess deregulate WNT4, from Wnt/β-catenin pathway, and engrailed homeobox 1 gene and increased TH and dopamine DRD1, adenosine ADORA2A and serotonin HTR7 receptors, whose over expression characterize early neuro-developmental processes.
Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain. rtorres.hulp@salud.madrid.org.|Servicio de Bioquímica, Edificio de Laboratorios, Planta 3, Hospital Universitario "La Paz", Paseo de la Castellana 261, 28046, Madrid, Spain. rtorres.hulp@salud.madrid.org.
R J
RJ
Torres
Department of Internal Medicine, Metabolic-Vascular Unit, La Paz University Hospital, IdiPaz, Madrid, Spain.
J G
JG
Puig
D000241:Adenosine / Q000378:metabolism; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000172:deficiency*; D007926:Lesch-Nyhan Syndrome / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000235:genetics; D014212:Tretinoin / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics; D060449:Wnt Signaling Pathway; D060528:Wnt4 Protein / Q000235:genetics*
C583260:DRD1 protein, human; C513076:EN1 protein, human; D018398:Homeodomain Proteins; D017447:Receptors, Dopamine D1; C555581:WNT4 protein, human; D060528:Wnt4 Protein; D014212:Tretinoin; D014446:Tyrosine 3-Monooxygenase; D007041:Hypoxanthine Phosphoribosyltransferase; D000241:Adenosine