title: A regulatory network controls nephrocan expression and midgut patterning.
abstract: Although many regulatory networks involved in defining definitive endoderm have been identified, the mechanisms through which these networks interact to pattern the endoderm are less well understood. To explore the mechanisms involved in midgut patterning, we dissected the transcriptional regulatory elements of nephrocan (Nepn), the earliest known midgut specific gene in mice. We observed that Nepn expression is dramatically reduced in Sox17(-/-) and Raldh2(-/-) embryos compared with wild-type embryos. We further show that Nepn is directly regulated by Sox17 and the retinoic acid (RA) receptor via two enhancer elements located upstream of the gene. Moreover, Nepn expression is modulated by Activin signaling, with high levels inhibiting and low levels enhancing RA-dependent expression. In Foxh1(-/-) embryos in which Nodal signaling is reduced, the Nepn expression domain is expanded into the anterior gut region, confirming that Nodal signaling can modulate its expression in vivo. Together, Sox17 is required for Nepn expression in the definitive endoderm, while RA signaling restricts expression to the midgut region. A balance of Nodal/Activin signaling regulates the anterior boundary of the midgut expression domain.
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, V5Z 1L3, Canada.
authors.forename: Juan
authors.initials: J
authors.lastname: Hou
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, V5Z 1L3, Canada.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84132-3401, USA.
authors.forename: Ranajeet S
authors.initials: RS
authors.lastname: Saund
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, V5Z 1L3, Canada.
authors.forename: Ping
authors.initials: P
authors.lastname: Xiang
authors.affiliation: Development, Aging and Regeneration Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Cunningham
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, V5Z 1L3, Canada Cell and Developmental Biology Program, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Yuyin
authors.initials: Y
authors.lastname: Yi
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, V5Z 1L3, Canada.
authors.forename: Olivia
authors.initials: O
authors.lastname: Alder
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, V5Z 1L3, Canada.
authors.forename: Daphne Y D
authors.initials: DY
authors.lastname: Lu
authors.affiliation: Cellular and Molecular Medicine, University of Ottawa, Ottawa K1H 8M5, Canada.
authors.forename: Joanne G A
authors.initials: JG
authors.lastname: Savory
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, V5Z 1L3, Canada.
authors.forename: Nicole A J
authors.initials: NA
authors.lastname: Krentz
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, V5Z 1L3, Canada.
authors.forename: Rachel
authors.initials: R
authors.lastname: Montpetit
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, V5Z 1L3, Canada.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Cullum
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, V5Z 1L3, Canada.
authors.forename: Nicole
authors.initials: N
authors.lastname: Hofs
authors.affiliation: Cellular and Molecular Medicine, University of Ottawa, Ottawa K1H 8M5, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Lohnes
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, V5Z 1L3, Canada Experimental Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: R Keith
authors.initials: RK
authors.lastname: Humphries
authors.affiliation: Goodman Cancer Research Centre, Department of Human Genetics, McGill University, Montreal, Quebec H2W 1S6, Canada.
authors.forename: Yojiro
authors.initials: Y
authors.lastname: Yamanaka
authors.affiliation: Development, Aging and Regeneration Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Gregg
authors.initials: G
authors.lastname: Duester
authors.affiliation: Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84132-3401, USA.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Saijoh
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, V5Z 1L3, Canada Cell and Developmental Biology Program, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada hoodless@bccrc.ca.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Hoodless
mesh_terms: D028341:Activins / Q000378:metabolism; D000445:Aldehyde Oxidoreductases / Q000378:metabolism; D000818:Animals; D019521:Body Patterning / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D004707:Endoderm / Q000502:physiology*; D041981:Gastrointestinal Tract / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D053263:Gene Regulatory Networks / Q000235:genetics / Q000502:physiology*; D005822:Genetic Vectors / Q000235:genetics; D006023:Glycoproteins / Q000378:metabolism*; D024002:HMGB Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008156:Luciferases; D051379:Mice; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D055760:SOXF Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D006023:Glycoproteins; D024002:HMGB Proteins; D036341:Intercellular Signaling Peptides and Proteins; D018168:Receptors, Retinoic Acid; D055760:SOXF Transcription Factors; C511606:Sox17 protein, mouse; C515971:nephrocan protein, mouse; D028341:Activins; D008156:Luciferases; D000445:Aldehyde Oxidoreductases; C470579:RALDH2 protein, mouse
keywords: Midgut definitive endoderm; Mouse; Nephrocan (Nepn); Nodal/Activin A; Retinoic acid; Sox17