Abstract
The Wnt signalling pathway plays a crucial role in the development of the nervous system. This signalling cascade is initiated upon binding of the secreted Wnt ligand to a member of the family of frizzled receptors. In the present study, we analysed the presence of frizzled-4 in the enteric nervous system of human infants. Frizzled-4 could be identified by immunohistochemistry in a subpopulation of enteric neuronal and glial cells in the small and large intestine. Detection of frizzled-4 in the tunica muscularis by RT-PCR confirmed this receptor's expression on the mRNA level. Interestingly, we observed distinct cell populations that co-expressed frizzled-4 with the intermediate filament protein nestin and the neurotrophin receptor p75NTR, which have been reported to be expressed in neural progenitor cells. Flow cytometry analysis revealed that 60% of p75NTR positive cells of the tunica muscularis were positive for frizzled-4. Additionally, in pathological samples of Hirschsprung's disease, the expression of this Wnt receptor correlated with the number of myenteric ganglion cells and decreased from normoganglionic to aganglionic areas of large intestine. The expression pattern of frizzled-4 indicates that this Wnt receptor could be involved in postnatal development and/or function of the enteric nervous system.
Highlights
Neurons and glial cells of the peripheral nervous system derive from neural crest stem cells (NCSCs) [1]
In pathological samples of Hirschsprung’s disease, the expression of this Wnt receptor correlated with the number of myenteric ganglion cells and decreased from normoganglionic to aganglionic areas of large intestine
Impairment of ENS development leads to incomplete colonization of the gut by NCSCs, resulting in peristaltic dysregulation, intestinal obstruction, and enterocolitis as observed in Hirschsprung’s disease (HSCR) [8,9,10]
Summary
Neurons and glial cells of the peripheral nervous system derive from neural crest stem cells (NCSCs) [1]. In humans migration of enteric neural crest cells takes place between gestational week 4 and gestational week 7 [4] During their journey along the gut a proportion of cells continues to proliferate, while others begin to differentiate [5] into neurons and glial cells in order to generate a complex neural network that coordinates bowel motility and is involved in regulation of its secretory activity, blood flow, and modulation of the immune system [6, 7]. Much effort has been put into research investigating the genetic regulation of neural crest development and its derivatives during the last decades This resulted in the identification of several major pathways regulating NCSC induction, migration, differentiation, and interconnection of developing neurons and glial cells [3, 11]. In concert with members of the bone morphogenic protein (BMP) family and fibroblast growth factors, Wnts regulate neural
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