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Title: Expression of PROKR1 and PROKR2 in Human Enteric Neural Precursor Cells and Identification of Sequence Variants Suggest a Role in HSCR
Authors: Ruiz-Ferrer, Macarena.
Torroglosa, Ana.
Nuñez-Torres, Rocio.
de Agustín, Juan Carlos
Antiñolo, Guillermo
Borrego, Salud
metadata.dc.contributor.authoraffiliation: [Ruiz-Ferrer,M; Torroglosa,A; Nuñez-Torres,R; Antiñolo,G; Borrego,S] Unidad de Gestión Clínica de Genética, Reproducción y Medicina Fetal, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío. CSIC. Universidad de Sevilla, Sevilla, Spain. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Sevilla, Spain. [de Agustín, JC] Unidad de Gestión Clínica de Cirugía Infantil, Hospital Universitario Virgen del Rocío, Sevilla, Spain
Keywords: Sistema Nervioso Entérico;Enfermedad de Hirschsprung
metadata.dc.subject.mesh: Medical Subject Headings::Diseases::Digestive System Diseases::Gastrointestinal Diseases::Intestinal Diseases::Colonic Diseases::Megacolon::Hirschsprung Disease
Medical Subject Headings::Diseases::Congenital, Hereditary, and Neonatal Diseases and Abnormalities::Congenital Abnormalities::Digestive System Abnormalities
Medical Subject Headings::Anatomy::Nervous System::Peripheral Nervous System::Autonomic Nervous System::Enteric Nervous System
Issue Date: 12-Aug-2011
Publisher: PLoS
Citation: Ruiz-Ferrer M, Torroglosa A, Núñez-Torres R, de Agustín JC, Antiñolo G, Borrego,S. Expression of PROKR1 and PROKR2 in Human Enteric Neural Precursor Cells and Identification of Sequence Variants Suggest a Role in HSCR. PLoS ONE 2011; 6(8): e23475.
Abstract: Background. The 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 Findings. In 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. Conclusions. Our 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.
metadata.dc.identifier.doi: 10.1371/journal.pone.0023475
ISSN: 1932-6203 (Online)
Appears in Collections:01- Artículos - Hospital Virgen del Rocío
01- Artículos - IBIS. Instituto de Biomedicina de Sevilla

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