MafB is required for islet beta cell maturation.
Pancreatic endocrine cell differentiation depends on transcription factors that also contribute in adult insulin and glucagon gene expression. Islet cell development was examined in mice lacking MafB, a transcription factor expressed in immature alpha (glucagon(+)) and beta (insulin(+)) cells and capable of activating insulin and glucagon expression in vitro. We observed that MafB(-/-) embryos had reduced numbers of insulin(+) and glucagon(+) cells throughout development, whereas the total number of endocrine cells was unchanged. Moreover, production of insulin(+) cells was delayed until embryonic day (E) 13.5 in mutant mice and coincided with the onset of MafA expression, a MafB-related activator of insulin transcription. MafA expression was only detected in the insulin(+) cell population in MafB mutants, whereas many important regulatory proteins continued to be expressed in insulin(-) beta cells. However, Pdx1, Nkx6.1, and GLUT2 were selectively lost in these insulin-deficient cells between E15.5 and E18.5. MafB appears to directly regulate transcription of these genes, because binding was observed within endogenous control region sequences. These results demonstrate that MafB plays a previously uncharacterized role by regulating transcription of key factors during development that are required for the production of mature alpha and beta cells.
Artner
Isabella
I
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, 723 Light Hall, Nashville, TN 37232, USA.
Blanchi
Bruno
B
Raum
Jeffrey C
JC
Guo
Min
M
Kaneko
Tomomi
T
Cordes
Sabine
S
Sieweke
Michael
M
Stein
Roland
R
D000818:Animals; D002454:Cell Differentiation; D005934:Glucagon / Q000378:metabolism; D051273:Glucose Transporter Type 2 / Q000502:physiology; D018398:Homeodomain Proteins / Q000502:physiology; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D051258:MafB Transcription Factor / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009154:Mutation; D013997:Time Factors; D015534:Trans-Activators / Q000502:physiology; D014158:Transcription, Genetic
D051273:Glucose Transporter Type 2; D018398:Homeodomain Proteins; D007328:Insulin; D051258:MafB Transcription Factor; C490406:Mafb protein, mouse; C491328:Nkx6-1 protein, mouse; C495682:Slc2a2 protein, mouse; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D005934:Glucagon