A switch from MafB to MafA expression accompanies differentiation to pancreatic beta-cells.
Major insulin gene transcription factors, such as PDX-1 or NeuroD1, have equally important roles in pancreatic development and the differentiation of pancreatic endocrine cells. Previously, we identified and cloned another critical insulin gene transcription factor MafA (RIPE3b1) and reported that other Maf factors were expressed in pancreatic endocrine cells. Maf factors are important regulators of cellular differentiation; to understand their role in differentiation of pancreatic endocrine cells, we analyzed the expression pattern of large-Maf factors in the pancreas of embryonic and adult mice. Ectopically expressed large-Maf factors, MafA, MafB, or cMaf, induced expression from insulin and glucagon reporter constructs, demonstrating a redundancy in their function. Yet in adult pancreas, cMaf was expressed in both alpha- and beta-cells, and MafA and MafB showed selective expression in the beta- and alpha-cells, respectively. Interestingly, during embryonic development, a significant proportion of MafB-expressing cells also expressed insulin. In embryos, MafB is expressed before MafA, and our results suggest that the differentiation of beta-cells proceeds through a MafB+ MafA- Ins+ intermediate cell to MafB- MafA+ Ins+ cells. Furthermore, the MafB to MafA transition follows induction of PDX-1 expression (Pdx-1(high)) in MafB+ Ins+ cells. We suggest that MafB may have a dual role in regulating embryonic differentiation of both beta- and alpha-cells while MafA may regulate replication/survival and function of beta-cells after birth. Thus, this redundancy in the function and expression of the large-Maf factors may explain the normal islet morphology observed in the MafA knockout mice at birth.
Nishimura
Wataru
W
Section of Islet Transplantation and Cell Biology, Joslin Diabetes Center, Boston, MA 02215, USA.
Kondo
Takuma
T
Salameh
Therese
T
El Khattabi
Ilham
I
Dodge
Rikke
R
Bonner-Weir
Susan
S
Sharma
Arun
A
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D049109:Cell Proliferation; D005260:Female; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D005934:Glucagon / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007328:Insulin / Q000096:biosynthesis / Q000235:genetics; D007515:Islets of Langerhans / Q000166:cytology* / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D051473:Maf Transcription Factors, Large / Q000235:genetics*; D051258:MafB Transcription Factor / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D007328:Insulin; D051473:Maf Transcription Factors, Large; D051258:MafB Transcription Factor; C485160:Mafa protein, mouse; C490406:Mafb protein, mouse; D012333:RNA, Messenger; D005934:Glucagon