例如:"lncRNA", "apoptosis", "WRKY"

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

Development. 2020 Nov 05;147(21)
Jamie Trott 1 , Yunus Alpagu 2 , Ee Kim Tan 3 , Mohammad Shboul 4 , Yousif Dawood 5 , Michael Elsy 6 , Heike Wollmann 7 , Vincent Tano 3 , Carine Bonnard 1 , Shermaine Eng 1 , Gunaseelan Narayanan 1 , Seetanshu Junnarkar 1 , Stephen Wearne 1 , James Strutt 1 , Aakash Kumar 3 , Lucian B Tomaz 3 , Pierre-Alexis Goy 7 , Slim Mzoughi 7 , Rachel Jennings 8 , Jaco Hagoort 9 , Ascia Eskin 10 , Hane Lee 10 , Stanley F Nelson 11 , Fawaz Al-Kazaleh 12 , Mohammad El-Khateeb 13 , Rajaa Fathallah 13 , Harsha Shah 14 , Jonathan Goeke 15 , Sarah R Langley 3 , Ernesto Guccione 7 , Neil Hanley 8 , Bernadette S De Bakker 9 , Bruno Reversade 16 , N Ray Dunn 3
Jamie Trott 1 , Yunus Alpagu 2 , Ee Kim Tan 3 , Mohammad Shboul 4 , Yousif Dawood 5 , Michael Elsy 6 , Heike Wollmann 7 , Vincent Tano 3 , Carine Bonnard 1 , Shermaine Eng 1 , Gunaseelan Narayanan 1 , Seetanshu Junnarkar 1 , Stephen Wearne 1 , James Strutt 1 , Aakash Kumar 3 , Lucian B Tomaz 3 , Pierre-Alexis Goy 7 , Slim Mzoughi 7 , Rachel Jennings 8 , Jaco Hagoort 9 , Ascia Eskin 10 , Hane Lee 10 , Stanley F Nelson 11 , Fawaz Al-Kazaleh 12 , Mohammad El-Khateeb 13 , Rajaa Fathallah 13 , Harsha Shah 14 , Jonathan Goeke 15 , Sarah R Langley 3 , Ernesto Guccione 7 , Neil Hanley 8 , Bernadette S De Bakker 9 , Bruno Reversade 16 , N Ray Dunn 3
+ et al

[No authors listed]

Author information
  • 1 Institute of Medical Biology, Agency for Science Technology and Research (A*STAR), 8A Biomedical Grove, #06-06 Immunos, 138648, Singapore.
  • 2 School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
  • 3 Lee Kong Chian School of Medicine, Nanyang Technological University, Clinical Sciences Building, 11 Mandalay Road, 308232, Singapore.
  • 4 Department of Medical Laboratory Sciences, Jordan University of Science and Technology, Irbid 2210, Jordan.
  • 5 Department of Obstetrics and Gynaecology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
  • 6 Faculty of Biology, Medicine & Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
  • 7 Institute of Molecular and Cellular Biology, Agency for Science Technology and Research (A*STAR), 61 Biopolis Drive, 138673, Singapore.
  • 8 Endocrinology Department, Manchester University NHS Foundation Trust, Grafton Street, Manchester M13 9WU, UK.
  • 9 Department of Medical Biology, Section Clinical Anatomy and Embryology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
  • 10 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
  • 11 Department of Pediatrics, UCLA Mattel Children's Hospital, Los Angeles, CA 90095, USA.
  • 12 Department of Obstetrics and Gynecology, University of Jordan, Amman 19241, Jordan.
  • 13 National Center for Diabetes, Endocrinology and Genetics, Amman 19241, Jordan.
  • 14 Department of Obstetrics and Gynaecology, Queen Charlotte's & Chelsea Hospital, Imperial College London, Du Cane Road, London W12 0HS, UK.
  • 15 Genome Institute of Singapore, Agency for Science Technology and Research (A*STAR), 60 Biopolis Street, 138672, Singapore.
  • 16 Koç University School of Medicine, Medical Genetics Department, Istanbul 34450, Turkey.

摘要


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 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.

KEYWORDS: Genetic disease, In vitro differentiation, Mitchell-Riley syndrome, Pancreas development, RFX6