Expression of PROKR1 and PROKR2 in Human Enteric Neural Precursor Cells and Identification of Sequence Variants Suggest a Role in HSCR

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 be...

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Authors: Ruiz Ferrer, Macarena, Torroglosa, Ana, Núñez-Torres, Rocío, Agustín, Juan Carlos de, Antiñolo Gil, Guillermo, Borrego, Salud
Format: article
Status:Published version
Publication Date:2011
Country:España
Institution:Universidad de Sevilla (US)
Repository:idUS. Depósito de Investigación de la Universidad de Sevilla
OAI Identifier:oai:idus.us.es:11441/114721
Online Access:https://hdl.handle.net/11441/114721
https://doi.org/10.1371/journal.pone.0023475
Access Level:Open access
Keyword:PROKR1
PROKR2
Enteric nervous system
Hirschsprung’s disease
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spelling Expression of PROKR1 and PROKR2 in Human Enteric Neural Precursor Cells and Identification of Sequence Variants Suggest a Role in HSCRRuiz Ferrer, MacarenaTorroglosa, AnaNúñez-Torres, RocíoAgustín, Juan Carlos deAntiñolo Gil, GuillermoBorrego, SaludPROKR1PROKR2Enteric nervous systemHirschsprung’s diseaseBackground: 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/ GFRa1/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.Fondo de Investigación Sanitaria, Spain (PI070080, PI1001290 and PI071315 for the E-Rare project)Consejería de Innovación Ciencia y Empresa de la Junta de Andalucía (CTS 2590)Consejería de Salud de la Junta de Andalucía (PI0249-2008)Public Library of ScienceCirugía2011info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/11441/114721https://doi.org/10.1371/journal.pone.0023475reponame:idUS. Depósito de Investigación de la Universidad de Sevillainstname:Universidad de Sevilla (US)InglésPLoS ONE, 6 (8), art. n.23475.PI070080PI1001290PI071315CTS 2590PI0249-2008https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0023475info:eu-repo/semantics/openAccessoai:idus.us.es:11441/1147212026-06-17T12:51:07Z
dc.title.none.fl_str_mv Expression of PROKR1 and PROKR2 in Human Enteric Neural Precursor Cells and Identification of Sequence Variants Suggest a Role in HSCR
title Expression of PROKR1 and PROKR2 in Human Enteric Neural Precursor Cells and Identification of Sequence Variants Suggest a Role in HSCR
spellingShingle Expression of PROKR1 and PROKR2 in Human Enteric Neural Precursor Cells and Identification of Sequence Variants Suggest a Role in HSCR
Ruiz Ferrer, Macarena
PROKR1
PROKR2
Enteric nervous system
Hirschsprung’s disease
title_short Expression of PROKR1 and PROKR2 in Human Enteric Neural Precursor Cells and Identification of Sequence Variants Suggest a Role in HSCR
title_full Expression of PROKR1 and PROKR2 in Human Enteric Neural Precursor Cells and Identification of Sequence Variants Suggest a Role in HSCR
title_fullStr Expression of PROKR1 and PROKR2 in Human Enteric Neural Precursor Cells and Identification of Sequence Variants Suggest a Role in HSCR
title_full_unstemmed Expression of PROKR1 and PROKR2 in Human Enteric Neural Precursor Cells and Identification of Sequence Variants Suggest a Role in HSCR
title_sort Expression of PROKR1 and PROKR2 in Human Enteric Neural Precursor Cells and Identification of Sequence Variants Suggest a Role in HSCR
dc.creator.none.fl_str_mv Ruiz Ferrer, Macarena
Torroglosa, Ana
Núñez-Torres, Rocío
Agustín, Juan Carlos de
Antiñolo Gil, Guillermo
Borrego, Salud
author Ruiz Ferrer, Macarena
author_facet Ruiz Ferrer, Macarena
Torroglosa, Ana
Núñez-Torres, Rocío
Agustín, Juan Carlos de
Antiñolo Gil, Guillermo
Borrego, Salud
author_role author
author2 Torroglosa, Ana
Núñez-Torres, Rocío
Agustín, Juan Carlos de
Antiñolo Gil, Guillermo
Borrego, Salud
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Cirugía
dc.subject.none.fl_str_mv PROKR1
PROKR2
Enteric nervous system
Hirschsprung’s disease
topic PROKR1
PROKR2
Enteric nervous system
Hirschsprung’s disease
description 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/ GFRa1/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.
publishDate 2011
dc.date.none.fl_str_mv 2011
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/11441/114721
https://doi.org/10.1371/journal.pone.0023475
url https://hdl.handle.net/11441/114721
https://doi.org/10.1371/journal.pone.0023475
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv PLoS ONE, 6 (8), art. n.23475.
PI070080
PI1001290
PI071315
CTS 2590
PI0249-2008
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0023475
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Public Library of Science
publisher.none.fl_str_mv Public Library of Science
dc.source.none.fl_str_mv reponame:idUS. Depósito de Investigación de la Universidad de Sevilla
instname:Universidad de Sevilla (US)
instname_str Universidad de Sevilla (US)
reponame_str idUS. Depósito de Investigación de la Universidad de Sevilla
collection idUS. Depósito de Investigación de la Universidad de Sevilla
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,198674

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