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RESEARCH ARTICLE| 08 April 2024
J. Guillermo Sanchez,
J. Guillermo Sanchez
1
Division of Developmental Biology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
2
Center for Stem Cell and Organoid Medicine (CuSTOM), University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
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Scott Rankin,
Scott Rankin
1
Division of Developmental Biology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
2
Center for Stem Cell and Organoid Medicine (CuSTOM), University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
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Emily Paul,
Emily Paul
1
Division of Developmental Biology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
2
Center for Stem Cell and Organoid Medicine (CuSTOM), University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
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Heather A. McCauley,
Heather A. McCauley
1
Division of Developmental Biology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
2
Center for Stem Cell and Organoid Medicine (CuSTOM), University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
3
Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
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Daniel O. Kechele,
Daniel O. Kechele
1
Division of Developmental Biology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
2
Center for Stem Cell and Organoid Medicine (CuSTOM), University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
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Jacob R. Enriquez
,
Jacob R. Enriquez
1
Division of Developmental Biology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
2
Center for Stem Cell and Organoid Medicine (CuSTOM), University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
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Nana-Hawa Jones,
Nana-Hawa Jones
4
Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
,
USA
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Siri A. W. Greeley,
Siri A. W. Greeley
5
Division of endocrinology, University of Chicago, Chicago, IL
,
USA
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Lisa Letourneau-Friedberg,
Lisa Letourneau-Friedberg
5
Division of endocrinology, University of Chicago, Chicago, IL
,
USA
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Aaron M. Zorn,
Aaron M. Zorn
1
Division of Developmental Biology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
2
Center for Stem Cell and Organoid Medicine (CuSTOM), University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
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Mansa Krishnamurthy,
Mansa Krishnamurthy
4
Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
,
USA
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James M. Wells
James M. Wells *
1
Division of Developmental Biology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
2
Center for Stem Cell and Organoid Medicine (CuSTOM), University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
4
Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
,
USA
*Author for correspondence: james.wells@cchmc.org
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Author and article information
J. Guillermo Sanchez
1
Division of Developmental Biology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
2
Center for Stem Cell and Organoid Medicine (CuSTOM), University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
Scott Rankin
1
Division of Developmental Biology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
2
Center for Stem Cell and Organoid Medicine (CuSTOM), University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
Emily Paul
1
Division of Developmental Biology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
2
Center for Stem Cell and Organoid Medicine (CuSTOM), University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
Heather A. McCauley
1
Division of Developmental Biology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
2
Center for Stem Cell and Organoid Medicine (CuSTOM), University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
3
Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
Daniel O. Kechele
1
Division of Developmental Biology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
2
Center for Stem Cell and Organoid Medicine (CuSTOM), University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
Jacob R. Enriquez
1
Division of Developmental Biology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
2
Center for Stem Cell and Organoid Medicine (CuSTOM), University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
Nana-Hawa Jones
4
Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
,
USA
Siri A. W. Greeley
5
Division of endocrinology, University of Chicago, Chicago, IL
,
USA
Lisa Letourneau-Friedberg
5
Division of endocrinology, University of Chicago, Chicago, IL
,
USA
Aaron M. Zorn
1
Division of Developmental Biology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
2
Center for Stem Cell and Organoid Medicine (CuSTOM), University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
Mansa Krishnamurthy
4
Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
,
USA
1
Division of Developmental Biology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
2
Center for Stem Cell and Organoid Medicine (CuSTOM), University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
,
USA
4
Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
,
USA
*Author for correspondence: james.wells@cchmc.org
Received: 09 Nov 2023
Accepted: 12 Mar 2024
Online ISSN: 1477-9129
Print ISSN: 0950-1991
Funding
Funding Group:
Award Group:
- Funder(s):
National Institutes of Health
- Award Id(s):
CA272903
- Funder(s):
Funding Group:
Award Group:
- Funder(s):
Allen Foundation
- Award Id(s):
Distinguished Investigator Award
- Funder(s):
Funding Group:
Award Group:
- Funder(s):
Shipley Foundation
- Funder(s):
© 2024. Published by The Company of Biologists Ltd
2024
http://www.biologists.com/user-licence-1-1/
Development dev.202529.
Article history
Received:
09 Nov 2023
Accepted:
12 Mar 2024
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Citation
J. Guillermo Sanchez, Scott Rankin, Emily Paul, Heather A. McCauley, Daniel O. Kechele, Jacob R. Enriquez, Nana-Hawa Jones, Siri A. W. Greeley, Lisa Letourneau-Friedberg, Aaron M. Zorn, Mansa Krishnamurthy, James M. Wells; RFX6 regulates human intestinal patterning and function upstream of PDX1. Development 2024; dev.202529. doi: https://doi.org/10.1242/dev.202529
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The gastrointestinal tract is complex and consists of multiple organs with unique functions. Rare gene mutations can cause congenital malformations of the human GI tract, although the molecular basis of these has been poorly studied. We identified a patient with compound-heterozygous mutations in RFX6 presenting with duodenal mal-rotation and atresia, implicating RFX6 in development of the proximal intestine. To identify how mutations in RFX6 impact intestinal patterning and function, we derived iPSCs from this patient to generate human intestinal organoids (HIOs). We identified that the duodenal HIOs and patient tissues had mixed regional identity, with gastric and ileal features. CRISPR-mediated correction of RFX6 restored duodenal identity. We then used gain- and loss-of-function and transcriptomic approaches in HIOs and Xenopus embryos to identify that PDX1 is a downstream transcriptional target of RFX6 required for duodenal development. However, RFX6 had additional PDX1-independent transcriptional targets involving multiple components of signaling pathways that are critical for establishing early regional identity in the GI tract. In summary, we have identified RFX6 as a key regulator in intestinal patterning that acts by regulating transcriptional and signaling pathways.
Keywords:
Endoderm patterning, Small Intestine, Organoids, Mitchell-Riley Syndrome, RFX6
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© 2024. Published by The Company of Biologists Ltd
2024
http://www.biologists.com/user-licence-1-1/
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