Mutations in the gene encoding the purine biosynthetic enzyme 
hypoxanthine-guanine phosphoribosyltransferase (HPRT) cause the intractable 
neurodevelopmental Lesch-Nyhan disease (LND) associated with aberrant 
development of brain dopamine pathways. In the current study, we have identified 
an increased expression of the microRNA miR181a in HPRT-deficient human 
dopaminergic SH-SY5Y neuroblastoma cells. Among the genes potentially regulated 
by miR181a are several known to be required for neural development, including 
Engrailed1 (En1), Engrailed2 (En2), Lmx1a and Brn2. We demonstrate that these 
genes are down-regulated in HPRT-deficient SH-SY5Y cells and that 
over-expression of miR181a significantly reduces endogenous expression of these 
genes and inhibits translation of luciferase plasmids bearing the En1/2 or Lmx1a 
3'UTR miRNA-binding elements. Conversely, inhibition of miR181a increases the 
expression of these genes and enhances translation of luciferase constructs 
bearing the En1/2 and Lmx1a 3'UTR miRNA-binding sequences. We also demonstrate 
that key neurodevelopmental genes (e.g. Nurr1, Pitx3, Wnt1 and Mash1) known to 
be functional partners of Lmx1a and Brn2 are also markedly down-regulated in 
SH-SY5Y cells over-expressing miR181a and in HPRT-deficient cells. Our findings 
in SH-SY5Y cells demonstrate that HPRT deficiency is accompanied by 
dysregulation of some of the important pathways that regulate the development of 
dopaminergic neurons and dopamine pathways and that this defect is associated 
with and possibly due at least partly to aberrant expression of miR181a. Because 
aberrant expression of miR181a is not as apparent in HPRT-deficient LND 
fibroblasts, the relevance of the SH-SY5Y neuroblastoma cells to human disease 
remains to be proven. Nevertheless, we propose that these pleiotropic 
neurodevelopment effects of miR181a may play a role in the pathogenesis of LND.