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Mitchell-Riley syndrome iPSCs exhibit reduced pancreatic endoderm differentiation due to a mutation in RFX6 .
- Source :
-
Development (Cambridge, England) [Development] 2020 Nov 05; Vol. 147 (21). Date of Electronic Publication: 2020 Nov 05. - Publication Year :
- 2020
-
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 <superscript>HA</superscript> 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.<br />Competing Interests: Competing interestsThe authors declare no competing or financial interests.<br /> (© 2020. Published by The Company of Biologists Ltd.)
- Subjects :
- Alleles
Base Sequence
Chromatin metabolism
Consanguinity
Diabetes Mellitus diagnostic imaging
Embryo, Mammalian metabolism
Embryonic Development
Family
Female
Gallbladder Diseases diagnostic imaging
Genome, Human
Humans
Induced Pluripotent Stem Cells metabolism
Intestinal Atresia diagnostic imaging
Male
Pedigree
Transcription, Genetic
Transcriptome genetics
X-Ray Microtomography
Cell Differentiation genetics
Diabetes Mellitus genetics
Diabetes Mellitus pathology
Endoderm embryology
Gallbladder Diseases genetics
Gallbladder Diseases pathology
Induced Pluripotent Stem Cells pathology
Intestinal Atresia genetics
Intestinal Atresia pathology
Mutation genetics
Pancreas embryology
Regulatory Factor X Transcription Factors genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1477-9129
- Volume :
- 147
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- Development (Cambridge, England)
- Publication Type :
- Academic Journal
- Accession number :
- 33033118
- Full Text :
- https://doi.org/10.1242/dev.194878