Abstract
Hirschsprung disease (HSCR) is attributed to a failure of neural crest derived cells to migrate, proliferate, differentiate or survive in the bowel wall during embryonic Enteric Nervous System (ENS) development. This process requires a wide and complex variety of molecules and signaling pathways which are activated by transcription factors. In an effort to better understand the etiology of HSCR, we have designed a study to identify new transcription factors participating in different stages of the colonization process. A differential expression study has been performed on a set of transcription factors using Neurosphere-like bodies from both HSCR and control patients. Differential expression levels were found for CDYL, MEIS1, STAT3 and PAX6. A significantly lower expression level for PAX6 in HSCR patients, would suit with the finding of an over-representation of the larger tandem (AC)m(AG)n repeats within the PAX6 promoter in HSCR patients, with the subsequent loss of protein P300 binding. Alternatively, PAX6 is a target for DNMT3B-dependant methylation, a process already proposed as a mechanism with a role in HSCR. Such decrease in PAX6 expression may influence in the proper function of signaling pathways involved in ENS with the confluence of additional genetic factors to the manifestation of HSCR phenotype.
Highlights
Several transcription factors are critical for the correct time course of ENS development
We have evaluated the gene expression profile of 48 transcription factors, all of them previously described as cell proliferation or differentiation modulators, which may be potential participants in the interactome network of enteric precursor cells during ENS development
This complex process is carefully regulated by interacting signals and transcription factors that confer cell characteristics in each moment of the ENS development, and it is accepted that failures in this process are responsible for HSCR pathogenesis
Summary
Several transcription factors are critical for the correct time course of ENS development. In enteric precursors from mice and human, Pax[3] is required for the activation of Ret transcription co-operatively acting with Sox1013,14. In an effort to better understand the etiology of HSCR and the signals required for a proper ENS development, we have designed a study to identify new transcription factors participating in different stages of the colonization process. With such purpose, we have performed a large-scale real-time PCR expression study of transcription factors participating in Embryonic Stem Cell networks that might be involved in ENS development, specially focusing on cell proliferation and/or differentiation process. For this study we have used human enteric precursor cells isolated from colon tissue of HSCR patients and control individuals as Neurospheres-like bodies (NLBs)
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