knock-down in enteric precursors reveals a possible mechanism by which this methyltransferase is involved in the enteric nervous system development and the onset of Hirschsprung disease.

Hirschsprung disease (HSCR, OMIM 142623) is a pathology that shows a lack of enteric ganglia along of the distal gastrointestinal tract. This aganglionosis is attributed to an abnormal proliferation, migration, differentiation and/or survival of enteric precursor cells (EPCs) derived from neural crest cells (NCCs) during the enteric nervous system (ENS) embryogenesis. DNMT3b methyltransferase is associated with NCCs development and has been shown to be implicated in ENS formation as well as in HSCR. In this study we have aimed to elucidate the specific mechanism underlying the DNMT3b role in such processes. We have performed the knockdown of expression (-KD) in enteric precursor cells (EPCs) to clarify its role on these cells . Moreover, we have analyzed several signaling pathways to determine the mechanisms responsible for the effect caused by -KD in EPCs. Our results seem to support that -KD promotes an increase EPCs proliferation that may be mediated by P53 and P21 activity, since both proteins were observed to be down-regulated in our -KD cultures. Moreover, we observed a down-regulation of and in HSCR patients. These results lead us to propose that DNMT3b could be involved in HSCR through P53 and P21 activity.