Cargando…

Insights into the etiology and physiopathology of MODY5/HNF1B pancreatic phenotype with a mouse model of the human disease

Maturity‐onset diabetes of the young type 5 (MODY5) is due to heterozygous mutations or deletion of HNF1B. No mouse models are currently available to recapitulate the human MODY5 disease. Here, we investigate the pancreatic phenotype of a unique MODY5 mouse model generated by heterozygous insertion...

Descripción completa

Detalles Bibliográficos
Autores principales: Quilichini, Evans, Fabre, Mélanie, Nord, Christoffer, Dirami, Thassadite, Le Marec, Axelle, Cereghini, Silvia, Pasek, Raymond C, Gannon, Maureen, Ahlgren, Ulf, Haumaitre, Cécile
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251562/
https://www.ncbi.nlm.nih.gov/pubmed/33527355
http://dx.doi.org/10.1002/path.5629
_version_ 1783717113806979072
author Quilichini, Evans
Fabre, Mélanie
Nord, Christoffer
Dirami, Thassadite
Le Marec, Axelle
Cereghini, Silvia
Pasek, Raymond C
Gannon, Maureen
Ahlgren, Ulf
Haumaitre, Cécile
author_facet Quilichini, Evans
Fabre, Mélanie
Nord, Christoffer
Dirami, Thassadite
Le Marec, Axelle
Cereghini, Silvia
Pasek, Raymond C
Gannon, Maureen
Ahlgren, Ulf
Haumaitre, Cécile
author_sort Quilichini, Evans
collection PubMed
description Maturity‐onset diabetes of the young type 5 (MODY5) is due to heterozygous mutations or deletion of HNF1B. No mouse models are currently available to recapitulate the human MODY5 disease. Here, we investigate the pancreatic phenotype of a unique MODY5 mouse model generated by heterozygous insertion of a human HNF1B splicing mutation at the intron‐2 splice donor site in the mouse genome. This Hnf1b ( sp2/+ ) model generated with targeted mutation of Hnf1b mimicking the c.544+1G>T (<IVS2nt+1G>T) mutation identified in humans, results in alternative transcripts and a 38% decrease of native Hnf1b transcript levels. As a clinical feature of MODY5 patients, the hypomorphic mouse model Hnf1b ( sp2/+ ) displays glucose intolerance. Whereas Hnf1b ( sp2/+ ) isolated islets showed no altered insulin secretion, we found a 65% decrease in pancreatic insulin content associated with a 30% decrease in total large islet volume and a 20% decrease in total β‐cell volume. These defects were associated with a 30% decrease in expression of the pro‐endocrine gene Neurog3 that we previously identified as a direct target of Hnf1b, showing a developmental etiology. As another clinical feature of MODY5 patients, the Hnf1b ( sp2/+ ) pancreases display exocrine dysfunction with hypoplasia. We observed chronic pancreatitis with loss of acinar cells, acinar‐to‐ductal metaplasia, and lipomatosis, with upregulation of signaling pathways and impaired acinar cell regeneration. This was associated with ductal cell deficiency characterized by shortened primary cilia. Importantly, the Hnf1b ( sp2/+ ) mouse model reproduces the pancreatic features of the human MODY5/HNF1B disease, providing a unique in vivo tool for molecular studies of the endocrine and exocrine defects and to advance basic and translational research. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
format Online
Article
Text
id pubmed-8251562
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher John Wiley & Sons, Ltd
record_format MEDLINE/PubMed
spelling pubmed-82515622021-07-06 Insights into the etiology and physiopathology of MODY5/HNF1B pancreatic phenotype with a mouse model of the human disease Quilichini, Evans Fabre, Mélanie Nord, Christoffer Dirami, Thassadite Le Marec, Axelle Cereghini, Silvia Pasek, Raymond C Gannon, Maureen Ahlgren, Ulf Haumaitre, Cécile J Pathol Original Papers Maturity‐onset diabetes of the young type 5 (MODY5) is due to heterozygous mutations or deletion of HNF1B. No mouse models are currently available to recapitulate the human MODY5 disease. Here, we investigate the pancreatic phenotype of a unique MODY5 mouse model generated by heterozygous insertion of a human HNF1B splicing mutation at the intron‐2 splice donor site in the mouse genome. This Hnf1b ( sp2/+ ) model generated with targeted mutation of Hnf1b mimicking the c.544+1G>T (<IVS2nt+1G>T) mutation identified in humans, results in alternative transcripts and a 38% decrease of native Hnf1b transcript levels. As a clinical feature of MODY5 patients, the hypomorphic mouse model Hnf1b ( sp2/+ ) displays glucose intolerance. Whereas Hnf1b ( sp2/+ ) isolated islets showed no altered insulin secretion, we found a 65% decrease in pancreatic insulin content associated with a 30% decrease in total large islet volume and a 20% decrease in total β‐cell volume. These defects were associated with a 30% decrease in expression of the pro‐endocrine gene Neurog3 that we previously identified as a direct target of Hnf1b, showing a developmental etiology. As another clinical feature of MODY5 patients, the Hnf1b ( sp2/+ ) pancreases display exocrine dysfunction with hypoplasia. We observed chronic pancreatitis with loss of acinar cells, acinar‐to‐ductal metaplasia, and lipomatosis, with upregulation of signaling pathways and impaired acinar cell regeneration. This was associated with ductal cell deficiency characterized by shortened primary cilia. Importantly, the Hnf1b ( sp2/+ ) mouse model reproduces the pancreatic features of the human MODY5/HNF1B disease, providing a unique in vivo tool for molecular studies of the endocrine and exocrine defects and to advance basic and translational research. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland. John Wiley & Sons, Ltd 2021-03-18 2021-05 /pmc/articles/PMC8251562/ /pubmed/33527355 http://dx.doi.org/10.1002/path.5629 Text en © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Papers
Quilichini, Evans
Fabre, Mélanie
Nord, Christoffer
Dirami, Thassadite
Le Marec, Axelle
Cereghini, Silvia
Pasek, Raymond C
Gannon, Maureen
Ahlgren, Ulf
Haumaitre, Cécile
Insights into the etiology and physiopathology of MODY5/HNF1B pancreatic phenotype with a mouse model of the human disease
title Insights into the etiology and physiopathology of MODY5/HNF1B pancreatic phenotype with a mouse model of the human disease
title_full Insights into the etiology and physiopathology of MODY5/HNF1B pancreatic phenotype with a mouse model of the human disease
title_fullStr Insights into the etiology and physiopathology of MODY5/HNF1B pancreatic phenotype with a mouse model of the human disease
title_full_unstemmed Insights into the etiology and physiopathology of MODY5/HNF1B pancreatic phenotype with a mouse model of the human disease
title_short Insights into the etiology and physiopathology of MODY5/HNF1B pancreatic phenotype with a mouse model of the human disease
title_sort insights into the etiology and physiopathology of mody5/hnf1b pancreatic phenotype with a mouse model of the human disease
topic Original Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251562/
https://www.ncbi.nlm.nih.gov/pubmed/33527355
http://dx.doi.org/10.1002/path.5629
work_keys_str_mv AT quilichinievans insightsintotheetiologyandphysiopathologyofmody5hnf1bpancreaticphenotypewithamousemodelofthehumandisease
AT fabremelanie insightsintotheetiologyandphysiopathologyofmody5hnf1bpancreaticphenotypewithamousemodelofthehumandisease
AT nordchristoffer insightsintotheetiologyandphysiopathologyofmody5hnf1bpancreaticphenotypewithamousemodelofthehumandisease
AT diramithassadite insightsintotheetiologyandphysiopathologyofmody5hnf1bpancreaticphenotypewithamousemodelofthehumandisease
AT lemarecaxelle insightsintotheetiologyandphysiopathologyofmody5hnf1bpancreaticphenotypewithamousemodelofthehumandisease
AT cereghinisilvia insightsintotheetiologyandphysiopathologyofmody5hnf1bpancreaticphenotypewithamousemodelofthehumandisease
AT pasekraymondc insightsintotheetiologyandphysiopathologyofmody5hnf1bpancreaticphenotypewithamousemodelofthehumandisease
AT gannonmaureen insightsintotheetiologyandphysiopathologyofmody5hnf1bpancreaticphenotypewithamousemodelofthehumandisease
AT ahlgrenulf insightsintotheetiologyandphysiopathologyofmody5hnf1bpancreaticphenotypewithamousemodelofthehumandisease
AT haumaitrececile insightsintotheetiologyandphysiopathologyofmody5hnf1bpancreaticphenotypewithamousemodelofthehumandisease