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Title page for ETD etd-10162015-094156

Type of Document Dissertation
Author Conrad, Elizabeth Elrod
Author's Email Address econrad86@gmail.com
URN etd-10162015-094156
Title Examining the roles of MafB in the pancreatic islet
Degree PhD
Department Molecular Physiology and Biophysics
Advisory Committee
Advisor Name Title
Maureen Gannon Committee Chair
Guoqiang Gu Committee Member
Mark Magnuson Committee Member
Roland Stein Committee Member
Wenbiao Chen Committee Member
  • pancreas
  • islets
  • diabetes
  • beta cells
  • transcription factors
Date of Defense 2015-06-19
Availability unrestricted
Analysis of MafB-/- mice suggested that this transcription factor was essential to islet α- and β-cell formation during development, although the postnatal physiological impact could not be studied because these mutants died due to problems in neural development. Pancreas-wide mutant mice were generated by crossing MafBfl/fl mice with transgenic Pancreatic and duodenal homeobox 1 (Pdx1) driven-Cre mice to compare the postnatal significance of MafB (MafBΔpanc) and MafA/B (MafABΔpanc) to deficiencies associated with the related, β-cell-enriched MafA mutant (MafAΔpanc). Insulin+ cell production and β-cell activity was merely delayed in MafBΔpanc islets until MafA was comprehensively expressed, although MafABΔpanc mice died soon after birth from hyperglycemia. However, glucose-induced glucagon secretion was compromised in adult MafBΔpanc islet α-cells. Based upon these results, we conclude that MafB alone is important to islet α-cell activity, and not β-cell function in rodents. Interestingly, a notable difference between mice and humans is that MAFB is coexpressed with MAFA in adult human islet β-cells. In fact, we found that non-human primate (NHP) islet α- and β-cells also produce MAFB, implying that MAFB represents a unique functional signature of the primate islet β-cell. Stimulated insulin secretion experiments in the human β-cell line, EndoC-βH1, suggest that MAFB impacts cAMP-induced insulin secretion in the primate β-cell.

Interestingly, MafB expression is silenced soon after birth in the rodent β-cell, only to be induced in a subset of maternal β-cells during pregnancy. Notably, the metabolic demands of pregnancy involve increases in β-cell mass and function. Our analysis of β-cell-specific MafB mutant (MafBΔβ) mice, generated by crossing MafBfl/fl mice with Rat Insulin Promoter (RIP)-Cre transgenic mice, suggests a specific role for MafB in β-cell proliferation during pregnancy. This thesis work sheds new light on the role of MafB in β-cells during pregnancy and its novel importance in primates.

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