Glial-derived growth factor signaling pathway in infantile hypertrophic pyloric stenosis.
OBJECTIVE
Glial-derived growth factor (GDNF), which is the ligand of RET is reported to be essential for the development of enteric nervous system. A GDNF knockout mouse model has shown that the gastric region is a critical passing site between GDNF-RET-independent neuroblasts (colonizing the esophagus) and GDNF-RET-dependent neuroblasts (colonizing the small and large bowel). The earliest GDNF site of production is the mesenchyme and the outer smooth muscle cell (SMC) layer of the developing bowel. In the mature gastrointestinal tract the presence of GDNF is restricted to enteric glial cells. The aim of this study was to investigate the expression of GDNF and RET in infantile hypertrophic pyloric stenosis (IHPS).


METHODS
Full-thickness muscle biopsy specimens were obtained from 8 IHPS patients at pyloromyotomy and from 8 age-matched controls without gastrointestinal disease. Indirect immunohistochemistry was performed using avidin-biotin-peroxidase complex method with anti-GDNF and anti-RET antibodies. Quantitative analysis was performed using sandwich-type enzyme-linked immunosorbent assay (ELISA) for GDNF.


RESULTS
GDNF- and RET-positive nerve fibers were absent or markedly reduced in IHPS compared with controls. GDNF was expressed strongly by smooth muscle cells of both muscular layers in IHPS, whereas no GDNF expression was detected in pyloric muscle of controls. The quantity of total GDNF in IHPS was significantly higher than in controls (P < .01).


CONCLUSIONS
The lack or markedly decreased number of GDNF-positive nerve fibers in IHPS supports the hypothesis of a selective immaturity of the enteric glia in the muscular layers in IHPS. The strong expression of GDNF in smooth muscle cells in IHPS and the increased levels of GDNF in IHPS suggest a compensatory mechanism by which the smooth muscle cells continue to produce GDNF until maturation of the enteric glial cells occurs.
Guarino
N
N
Children's Research Centre, Our Lady's Hospital for Sick Children, Dublin, Ireland.
Shima
H
H
Oue
T
T
Puri
P
P
D029721:Drosophila Proteins; D004797:Enzyme-Linked Immunosorbent Assay; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006801:Humans; D006984:Hypertrophy; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D009130:Muscle, Smooth / Q000737:chemistry / Q000294:innervation; D009197:Myenteric Plexus / Q000737:chemistry; D009414:Nerve Growth Factors / Q000032:analysis*; D009419:Nerve Tissue Proteins / Q000032:analysis*; D011518:Proto-Oncogene Proteins / Q000032:analysis; D051096:Proto-Oncogene Proteins c-ret; D011707:Pyloric Stenosis / Q000151:congenital* / Q000378:metabolism*; D011708:Pylorus / Q000737:chemistry / Q000294:innervation; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis; D015398:Signal Transduction
D029721:Drosophila Proteins; C495039:GDNF protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila