title: Targeted deletion of a cis-regulatory region reveals differential gene dosage requirements for Pdx1 in foregut organ differentiation and pancreas formation.
abstract: Pdx1 (IPF-1 in humans, which is altered in MODY-4) is essential for pancreas development and mature beta-cell function. Pdx1 is expressed dynamically within the developing foregut, but how its expression characteristics are linked to the various steps of organ specification, differentiation, and function is unknown. Deletion of a conserved enhancer region (Area I-II-III) from Pdx1 produced a hypomorphic allele (Pdx1(DeltaI-II-III)) with altered timing and level of expression, which was studied in combination with wild-type and protein-null alleles. Lineage labeling in homozygous Area I-II-III deletion mutants (Pdx1(DeltaI-II-III/DeltaI-II-III)) revealed lack of ventral pancreatic bud specification and early-onset hypoplasia in the dorsal bud. Acinar tissue formed in the hypoplastic dorsal bud, but endocrine maturation was greatly impaired. While Pdx1(-/-) (protein-null) mice have nonpancreatic abnormalities (e.g., distorted pylorus, absent Brunner's glands), these structures formed normally in Pdx1(DeltaI-II-III/DeltaI-II-III) and Pdx1(DeltaI-II-III/-) mice. Surprisingly, heterozygous (Pdx1(+/DeltaI-II-III)) mice had abnormal islets and a more severe prediabetic condition than Pdx1(+/-) mice. These findings provide in vivo evidence of the differential requirements for the level of Pdx1 gene activity in the specification and differentiation of the various organs of the posterior foregut, as well as in pancreas and gut endocrine cell differentiation.
authors.affiliation: Vanderbilt Program in Developmental Biology and Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2175, USA.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Fujitani
authors.forename: Shuko
authors.initials: S
authors.lastname: Fujitani
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Boyer
authors.forename: Maureen
authors.initials: M
authors.lastname: Gannon
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Kawaguchi
authors.forename: Michael
authors.initials: M
authors.lastname: Ray
authors.forename: Masakazu
authors.initials: M
authors.lastname: Shiota
authors.forename: Roland W
authors.initials: RW
authors.lastname: Stein
authors.forename: Mark A
authors.initials: MA
authors.lastname: Magnuson
authors.forename: Christopher V E
authors.initials: CV
authors.lastname: Wright
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D017124:Conserved Sequence; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D019858:Enteroendocrine Cells / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D038081:Organogenesis / Q000235:genetics; D010179:Pancreas / Q000196:embryology* / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics* / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein