Publication:
Mitchell-Riley syndrome iPSCs exhibit reduced pancreatic endoderm differentiation due to a mutation in RFX6

Thumbnail Image

Departments

Organizational Unit

School / College / Institute

Organizational Unit
SCHOOL OF MEDICINE
Upper Org Unit

Program

KU Authors

Co-Authors

Trott, Jamie
Alpagu, Yunus
Tan, Ee Kim
Shboul, Mohammad
Dawood, Yousif
Elsy, Michael
Wollmann, Heike
Tano, Vincent
Bonnard, Carine
Eng, Shermaine

Publication Date

Language

Embargo Status

NO

Journal Title

Journal ISSN

Volume Title

Alternative Title

Abstract

Mitchell-Riley syndrome (MRS) is caused by recessive mutations in the regulatory factor X6 gene (RFX6) and is characterised by pancreatic hypoplasia and neonatal diabetes. To determine why individuals with MRS specifically lack pancreatic endocrine cells, we micro-CT imaged a 12-week-old foetus homozygous for the nonsense mutation RFX6 c.1129C>T, which revealed loss of the pancreas body and tail. From this foetus, we derived iPSCs and show that differentiation of these cells in vitro proceeds normally until generation of pancreatic endoderm, which is significantly reduced. We additionally generated an RFX6 H A reporter allele by gene targeting in wild-type H9 cells to precisely define RFX6 expression and in parallel performed in situ hybridisation for RFX6 in the dorsal pancreatic bud of a Carnegie stage 14 human embryo. Both in vitro and in vivo, we find that RFX6 specifically labels a subset of PDX1-expressing pancreatic endoderm. In summary, RFX6 is essential for efficient differentiation of pancreatic endoderm, and its absence in individuals with MRS specifically impairs formation of endocrine cells of the pancreas head and tail.

Source

Publisher

The Company of Biologists

Subject

Developmental biology

Citation

Has Part

Source

Development

Book Series Title

Edition

DOI

10.1242/dev.194878

item.page.datauri

Link

Rights

Copyrights Note

Endorsement

Review

Supplemented By

Referenced By

0

Views

5

Downloads

View PlumX Details