title: Lack of Prox1 Downregulation Disrupts the Expansion and Maturation of Postnatal Murine β-Cells.
abstract: Transcription factor expression fluctuates during β-cell ontogeny, and disruptions in this pattern can affect the development or function of those cells. Here we uncovered that murine endocrine pancreatic progenitors express high levels of the homeodomain transcription factor Prox1, whereas both immature and mature β-cells scarcely express this protein. We also investigated if sustained Prox1 expression is incompatible with β-cell development or maintenance using transgenic mouse approaches. We discovered that Prox1 upregulation in mature β-cells has no functional consequences; in contrast, Prox1 overexpression in immature β-cells promotes acute fasting hyperglycemia. Using a combination of immunostaining and quantitative and comparative gene expression analyses, we determined that Prox1 upregulation reduces proliferation, impairs maturation, and enables apoptosis in postnatal β-cells. Also, we uncovered substantial deficiency in β-cells that overexpress Prox1 of the key regulator of β-cell maturation MafA, several MafA downstream targets required for glucose-stimulated insulin secretion, and genes encoding important components of FGF signaling. Moreover, knocking down PROX1 in human EndoC-βH1 β-cells caused increased expression of many of these same gene products. These and other results in our study indicate that reducing the expression of Prox1 is beneficial for the expansion and maturation of postnatal β-cells.
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Leena
authors.initials: L
authors.lastname: Paul
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical School, Nashville, TN.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Walker
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Yiannis
authors.initials: Y
authors.lastname: Drosos
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical School, Nashville, TN.
authors.forename: Holly A
authors.initials: HA
authors.lastname: Cyphert
authors.affiliation: Hartwell Center for Bioinformatics & Biotechnology, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Neale
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical School, Nashville, TN.
authors.forename: Roland
authors.initials: R
authors.lastname: Stein
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Jack
authors.initials: J
authors.lastname: South
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Gerard
authors.initials: G
authors.lastname: Grosveld
authors.affiliation: Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Herrera
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL beatriz.sosa-pineda@northwestern.edu.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Sosa-Pineda
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D003198:Computer Simulation; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D005951:Glucose Tolerance Test; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics*; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D051473:Maf Transcription Factors, Large / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D018398:Homeodomain Proteins; D007328:Insulin; D051473:Maf Transcription Factors, Large; C485160:Mafa protein, mouse; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein