Threshold-Dependent Cooperativity of Pdx1 and Oc1 in Pancreatic Progenitors Establishes Competency for Endocrine Differentiation and β-Cell Function

TY - JOUR

T1 - Threshold-Dependent Cooperativity of Pdx1 and Oc1 in Pancreatic Progenitors Establishes Competency for Endocrine Differentiation and β-Cell Function

AU - Henley, Kathryn D

AU - Stanescu, Diana E

AU - Kropp, Peter A

AU - Wright, Christopher V E

AU - Won, Kyoung-Jae

AU - Stoffers, Doris A

AU - Gannon, Maureen

N1 - Published by Elsevier Inc.

PY - 2016/6/21

Y1 - 2016/6/21

N2 - Pdx1 and Oc1 are co-expressed in multipotent pancreatic progenitors and regulate the pro-endocrine gene Neurog3. Their expression diverges in later organogenesis, with Oc1 absent from hormone+ cells and Pdx1 maintained in mature β cells. In a classical genetic test for cooperative functional interactions, we derived mice with combined Pdx1 and Oc1 heterozygosity. Endocrine development in double-heterozygous pancreata was normal at embryonic day (E)13.5, but defects in specification and differentiation were apparent at E15.5, the height of the second wave of differentiation. Pancreata from double heterozygotes showed alterations in the expression of genes crucial for β-cell development and function, decreased numbers and altered allocation of Neurog3-expressing endocrine progenitors, and defective endocrine differentiation. Defects in islet gene expression and β-cell function persisted in double heterozygous neonates. These results suggest that Oc1 and Pdx1 cooperate prior to their divergence, in pancreatic progenitors, to allow for proper differentiation and functional maturation of β cells.

AB - Pdx1 and Oc1 are co-expressed in multipotent pancreatic progenitors and regulate the pro-endocrine gene Neurog3. Their expression diverges in later organogenesis, with Oc1 absent from hormone+ cells and Pdx1 maintained in mature β cells. In a classical genetic test for cooperative functional interactions, we derived mice with combined Pdx1 and Oc1 heterozygosity. Endocrine development in double-heterozygous pancreata was normal at embryonic day (E)13.5, but defects in specification and differentiation were apparent at E15.5, the height of the second wave of differentiation. Pancreata from double heterozygotes showed alterations in the expression of genes crucial for β-cell development and function, decreased numbers and altered allocation of Neurog3-expressing endocrine progenitors, and defective endocrine differentiation. Defects in islet gene expression and β-cell function persisted in double heterozygous neonates. These results suggest that Oc1 and Pdx1 cooperate prior to their divergence, in pancreatic progenitors, to allow for proper differentiation and functional maturation of β cells.

KW - Animals

KW - Basic Helix-Loop-Helix Transcription Factors/metabolism

KW - Cell Count

KW - Cell Differentiation

KW - Embryo, Mammalian/cytology

KW - Gene Dosage

KW - Gene Expression Regulation, Developmental

KW - Gene Ontology

KW - Gene Regulatory Networks

KW - Glucose/metabolism

KW - Hepatocyte Nuclear Factor 6/metabolism

KW - Heterozygote

KW - Homeodomain Proteins/metabolism

KW - Homeostasis/genetics

KW - Insulin-Secreting Cells/cytology

KW - Mice

KW - Multigene Family

KW - Nerve Tissue Proteins/metabolism

KW - Stem Cells/cytology

KW - Trans-Activators/metabolism

KW - Weaning

U2 - 10.1016/j.celrep.2016.05.040

DO - 10.1016/j.celrep.2016.05.040

M3 - Journal article

C2 - 27292642

SN - 2639-1856

VL - 15

SP - 2637

EP - 2650

JO - Cell Reports

JF - Cell Reports

IS - 12

ER -