Downregulation of Protein Tyrosine Phosphatase Receptor Type R Accounts for the Progression of Hirschsprung Disease

Abstract

Hirschsprung disease (HSCR) is a common developmental disorder of the enteric nervous system (ENS). However, the disease mechanisms have not been fully elucidated. To better understand the etiology of HSCR, the role and mechanism of HSCR associated PTPRR (protein tyrosine phosphatase receptor-type R) in the multipotency of ENS progenitors and ENS development were explored. In the present study, the downregulated PTPRR expression in HSCR was reflected by microarray and validated by real-time PCR analyses. Moreover, PTPRR protein was mainly expressed in the cytoplasmic area of primary cultured ENS progenitors (Enteric neural crest cells, ENCCs) and significantly decreased after differentiation induction, which implies the anti-differentiation role in ENCCs. Further study employed an adenovirus transfection system. After genetic modulation, the ENCCs maintained undifferentiated patterns even in GDNF (Glial cell-line derived neurotrophic factor)-mediated directional differentiation, as well as significantly increased EdU positive immunofluorescence in the PTPRR overexpressing group while the development of the ENS was stunted in the PTPRR knockdown fetal gut. Moreover, the expression of ERK1/2 activated by GDNF was significantly decreased as reflected by western-blot or immunofluorescence analyses after genetic modulation in the PTPRR overexpressing group, which suggests the potential mechanism in regulating the MAPK/ERK1/2 pathway. Taken together, These data support the idea that PTPRR may ensure a certain number of neural precursor cells by inhibiting ENCC overt differentiation and maintaining ENCC proliferation, which is considered to be the multipotency of ENCCs, and eventually participate in the development of the ENS, and establish PTPRR protein as negative regulator of MAPK/ERK1/2 signaling cascades in neuronal differentiation and demonstrate their involvement in the pathophysiology of HSCR.

Bioinformatics Analysis of Differentially Expressed miRNAs and Their Related Genes From Plasma-Derived Exosomes in TCA

“…HSCR is a common congenital disease in infants, which is characterized by the disturbance of intestinal motility [14]. However, there is no precise mechanism to explain the related pathophysiology of HSCR [15]. In this study, the differentially expressed miRNAs were screened out by comparing plasma-derived exosomes of healthy groups and HSCR groups, using comprehensive bioinformatics analysis to investigate the pathogenesis of HSCR.…”

Differentiation and Subtype Specification of Enteric Neurons: Current Knowledge of Transcription Factors, Signaling Molecules and Signaling Pathways Involved

“…While the vagal NCCs are colonizing the entire length of the GI tract, the sacral NCCs show a small contribution to the ENS by colonizing the postumbilical region [9,18]. Between embryonic day (E) 8.5 and 9.5 in mice, and before the 4 th week of pregnancy in humans, NCCs delaminate from the neural crest and become progenitors for multiple cell types among which the enteric neurons [11,[19][20][21]. After delamination, the vagal NCCs start to migrate towards the developing foregut.…”

“…This leads to a number of congenital enteric neuropathies, such as Hirschsprung's disease (HSCR) [21,22,30]. HSCR is an enteric neuropathy which occurs in 1:5000 live-births and is characterized by aganglionosis along variable lengths of the distal intestine [10,20]. In most cases (80-90%), aganglionosis is affecting the rectum and the distal part of the sigmoid colon [20,21,32].…”

“…HSCR is an enteric neuropathy which occurs in 1:5000 live-births and is characterized by aganglionosis along variable lengths of the distal intestine [10,20]. In most cases (80-90%), aganglionosis is affecting the rectum and the distal part of the sigmoid colon [20,21,32]. HSCR is caused by the failing of ENCCs to colonize the distal part of the intestinal tract during gestation (weeks 4 to 12 of human embryonic development).…”

“…On the other hand, forced expression has been suggested to impose NCC-like characteristics in in vivo neural tissue [42]. The expression of Sox10 will be downregulated as cells differentiate into enteric neurons [11,20,44]. While the Sox10-expression is decreasing in certain cells, in some other cells the expression remains.…”