No neuronal loss, but alterations of the GDNF system in asymptomatic diverticulosis.
BACKGROUND
Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor known to promote the survival and maintenance of neurons not only in the developing but also in the adult enteric nervous system. As diverticular disease (DD) is associated with reduced myenteric neurons, alterations of the GDNF system were studied in asymptomatic diverticulosis (diverticulosis) and DD.


METHODS
Morphometric analysis for quantifying myenteric ganglia and neurons were assessed in colonic full-thickness sections of patients with diverticulosis and controls. Samples of tunica muscularis (TM) and laser-microdissected myenteric ganglia from patients with diverticulosis, DD and controls were analyzed for mRNA expression levels of GDNF, GFRA1, and RET by RT-qPCR. Myenteric protein expression of both receptors was quantified by fluorescence-immunohistochemistry of patients with diverticulosis, DD, and controls.


RESULTS
Although no myenteric morphometric alterations were found in patients with diverticulosis, GDNF, GFRA1 and RET mRNA expression was down-regulated in the TM of patients with diverticulosis as well as DD. Furthermore GFRA1 and RET myenteric plexus mRNA expression of patients with diverticulosis and DD was down-regulated, whereas GDNF remained unaltered. Myenteric immunoreactivity of the receptors GFRα1 and RET was decreased in both asymptomatic diverticulosis and DD patients.


CONCLUSIONS
Our data provide evidence for an impaired GDNF system at gene and protein level not only in DD but also during early stages of diverticula formation. Thus, the results strengthen the idea of a disturbed GDNF-responsiveness as contributive factor for a primary enteric neuropathy involved in the pathogenesis and disturbed intestinal motility observed in DD.
Institute of Anatomy, Kiel University, Kiel, Germany.
Martina
http://orcid.org/0000-0002-0244-9333
M
Barrenschee
Institute of Anatomy, Kiel University, Kiel, Germany.
Thilo
T
Wedel
Institute of Anatomy, Kiel University, Kiel, Germany.
Christina
C
Lange
Institute of Anatomy, Kiel University, Kiel, Germany.
Ines
I
Hohmeier
Institute of Anatomy, Kiel University, Kiel, Germany.
François
F
Cossais
Department of Pathology, Städtisches Krankenhaus Kiel, Kiel, Germany.
Michael
M
Ebsen
Department of Surgery, Städtisches Krankenhaus Kiel, Kiel, Germany.
Ilka
I
Vogel
Institute of Anatomy, Kiel University, Kiel, Germany.
Martina
M
Böttner
D000368:Aged; D016022:Case-Control Studies; D003106:Colon / Q000294:innervation / Q000473:pathology; D004240:Diverticulum / Q000473:pathology / Q000503:physiopathology*; D005455:Fluorescent Antibody Technique; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000502:physiology*; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000502:physiology; D006801:Humans; D061346:Laser Capture Microdissection; D008297:Male; D009197:Myenteric Plexus / Q000473:pathology; D051096:Proto-Oncogene Proteins c-ret / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction
C494987:GFRA1 protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human