Abstract
BackgroundThe enteric nervous system (ENS) is entirely derived from neural crest and its normal development is regulated by specific molecular pathways. Failure in complete ENS formation results in aganglionic gut conditions such as Hirschsprung's disease (HSCR). Recently, PROKR1 expression has been demonstrated in mouse enteric neural crest derived cells and Prok-1 was shown to work coordinately with GDNF in the development of the ENS.Principal FindingsIn the present report, ENS progenitors were isolated and characterized from the ganglionic gut from children diagnosed with and without HSCR, and the expression of prokineticin receptors was examined. Immunocytochemical analysis of neurosphere-forming cells demonstrated that both PROKR1 and PROKR2 were present in human enteric neural crest cells. In addition, we also performed a mutational analysis of PROKR1, PROKR2, PROK1 and PROK2 genes in a cohort of HSCR patients, evaluating them for the first time as susceptibility genes for the disease. Several missense variants were detected, most of them affecting highly conserved amino acid residues of the protein and located in functional domains of both receptors, which suggests a possible deleterious effect in their biological function.ConclusionsOur results suggest that not only PROKR1, but also PROKR2 might mediate a complementary signalling to the RET/GFRα1/GDNF pathway supporting proliferation/survival and differentiation of precursor cells during ENS development. These findings, together with the detection of sequence variants in PROKR1, PROK1 and PROKR2 genes associated to HSCR and, in some cases in combination with RET or GDNF mutations, provide the first evidence to consider them as susceptibility genes for HSCR.
Highlights
The enteric nervous system (ENS) is composed of a large number of neurons and glia, which are organised into interconnected ganglia distributed throughout the gastrointestinal tract
Our results suggest that PROKR1, and PROKR2 might mediate a complementary signalling to the RET/ GFRa1/glial cell derived neurotrophic factor (GDNF) pathway supporting proliferation/survival and differentiation of precursor cells during ENS development
These findings, together with the detection of sequence variants in PROKR1, PROK1 and PROKR2 genes associated to Hirschsprung’s disease (HSCR) and, in some cases in combination with RET or GDNF mutations, provide the first evidence to consider them as susceptibility genes for HSCR
Summary
The enteric nervous system (ENS) is composed of a large number of neurons and glia, which are organised into interconnected ganglia distributed throughout the gastrointestinal tract It is originated from neural crest cells (NCCs), that invade the foregut mesenchyme during embryogenesis and migrate in a rostrocaudal direction to extensively colonize the entire length of the gut [1]. HSCR, with an incidence of 1:5000 live births, is the most common developmental disorder of the ENS, characterized by its incomplete formation and the absence of enteric ganglia in a variable segment of distal bowel This leads to peristaltic misregulation and tonic contraction within the affected gut, causing intestinal obstruction [2]. PROKR1 expression has been demonstrated in mouse enteric neural crest derived cells and Prok-1 was shown to work coordinately with GDNF in the development of the ENS
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