title: Gestational Diabetes Mellitus From Inactivation of Prolactin Receptor and MafB in Islet β-Cells.
abstract: β-Cell proliferation and expansion during pregnancy are crucial for maintaining euglycemia in response to increased metabolic demands placed on the mother. Prolactin and placental lactogen signal through the prolactin receptor (PRLR) and contribute to adaptive β-cell responses in pregnancy; however, the in vivo requirement for PRLR signaling specifically in maternal β-cell adaptations remains unknown. We generated a floxed allele of Prlr, allowing conditional loss of PRLR in β-cells. In this study, we show that loss of PRLR signaling in β-cells results in gestational diabetes mellitus (GDM), reduced β-cell proliferation, and failure to expand β-cell mass during pregnancy. Targeted PRLR loss in maternal β-cells in vivo impaired expression of the transcription factor Foxm1, both G1/S and G2/M cyclins, tryptophan hydroxylase 1 (Tph1), and islet serotonin production, for which synthesis requires Tph1. This conditional system also revealed that PRLR signaling is required for the transient gestational expression of the transcription factor MafB within a subset of β-cells during pregnancy. MafB deletion in maternal β-cells also produced GDM, with inadequate β-cell expansion accompanied by failure to induce PRLR-dependent target genes regulating β-cell proliferation. These results unveil molecular roles for PRLR signaling in orchestrating the physiologic expansion of maternal β-cells during pregnancy.
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA Division of Endocrinology, Gerontology and Metabolism, Department of Medicine, Stanford University School of Medicine, Stanford, CA.
authors.forename: Ronadip R
authors.initials: RR
authors.lastname: Banerjee
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
authors.forename: Holly A
authors.initials: HA
authors.lastname: Cyphert
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Walker
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Harini
authors.initials: H
authors.lastname: Chakravarthy
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Heshan
authors.initials: H
authors.lastname: Peiris
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Xueying
authors.initials: X
authors.lastname: Gu
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Conrad
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, MA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Goodrich
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
authors.forename: Roland W
authors.initials: RW
authors.lastname: Stein
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA seungkim@stanford.edu.
authors.forename: Seung K
authors.initials: SK
authors.lastname: Kim
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D056751:Cyclin A2 / Q000235:genetics; D056744:Cyclin B1 / Q000235:genetics; D056765:Cyclin B2 / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics; D056742:Cyclin D2 / Q000235:genetics; D016640:Diabetes, Gestational / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D000072278:Forkhead Box Protein M1 / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051258:MafB Transcription Factor / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011247:Pregnancy; D011981:Receptors, Prolactin / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000378:metabolism
chemical_list: C508184:CCNA2 protein, mouse; C534700:Ccnb1 protein, mouse; C503759:Ccnb2 protein, mouse; C530105:Ccnd1 protein, mouse; C486196:Ccnd2 protein, mouse; D056751:Cyclin A2; D056744:Cyclin B1; D056765:Cyclin B2; D056742:Cyclin D2; D000072278:Forkhead Box Protein M1; C491524:Foxm1 protein, mouse; D007328:Insulin; D051258:MafB Transcription Factor; C490406:Mafb protein, mouse; D011981:Receptors, Prolactin; D019938:Cyclin D1; D012701:Serotonin; C487801:Tph1 protein, mouse; D014365:Tryptophan Hydroxylase