Replacement of Rbpj with Rbpjl in the PTF1 complex controls the final maturation of pancreatic acinar cells.
OBJECTIVE
The mature pancreatic acinar cell is dedicated to the production of very large amounts of digestive enzymes. The early stages of pancreatic development require the Rbpj form of the trimeric Pancreas Transcription Factor 1 complex (PTF1-J). As acinar development commences, Rbpjl gradually replaces Rbpj; in the mature pancreas, PTF1 contains Rbpjl (PTF1-L). We investigated whether PTF1-L controls the expression of genes that complete the final stage of acinar differentiation.


METHODS
We analyzed acinar development and transcription in mice with disrupted Rbpjl (Rbpjl(ko/ko) mice). We performed comprehensive analyses of the messenger RNA population and PTF1 target genes in pancreatic acinar cells from these and wild-type mice.


RESULTS
In Rbpjl(ko/ko) mice, acinar differentiation was incomplete and characterized by decreased expression (as much as 99%) of genes that encode digestive enzymes or proteins of regulated exocytosis and mitochondrial metabolism. Whereas PTF1-L bound regulatory sites of genes in normal adult pancreatic cells, the embryonic form (PTF1-J) persisted in the absence of Rbpjl and replaced PTF1-L; the extent of replacement determined gene expression levels. Loss of PTF1-L reduced expression (>2-fold) of only about 50 genes, 90% of which were direct targets of PTF1-L. The magnitude of the effects on individual digestive enzyme genes correlated with the developmental timing of gene activation. Absence of Rbpjl increased pancreatic expression of liver-restricted messenger RNA.


CONCLUSIONS
Replacement of Rbpj by Rbpjl in the PTF1 complex drives acinar differentiation by maximizing secretory protein synthesis, stimulating mitochondrial metabolism and cytoplasmic creatine-phosphate energy stores, completing the packaging and secretory apparatus, and maintaining acinar-cell homeostasis.
Masui
Toshihiko
T
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148, USA.
Swift
Galvin H
GH
Deering
Tye
T
Shen
Chengcheng
C
Coats
Ward S
WS
Long
Qiaoming
Q
Elsässer
Hans-Peter
HP
Magnuson
Mark A
MA
MacDonald
Raymond J
RJ
D000818:Animals; D002454:Cell Differentiation; D005786:Gene Expression Regulation; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D046790:Pancreas, Exocrine / Q000166:cytology*; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D014157:Transcription Factors / Q000502:physiology*
D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D012333:RNA, Messenger; C497571:Rbpj protein, mouse; D014157:Transcription Factors; C062602:transcription factor PTF1
Genes Dev. 2008 Jan 15;22(2):166-78
18198335
Genes Dev. 2007 Oct 15;21(20):2629-43
17938243
Biochim Biophys Acta. 1978 Nov 2;513(2):255-67
718894
Proc Natl Acad Sci U S A. 1986 Jan;83(1):110-4
2417232
Biochem Biophys Res Commun. 1985 Mar 29;127(3):937-42
3885943
Genomics. 2001 Aug;76(1-3):89-98
11549321
J Biol Chem. 2002 Dec 27;277(52):50725-33
12401800
Biochem J. 2005 Feb 1;385(Pt 3):721-7
15462671
J Biochem. 1999 Oct;126(4):738-47
10502683
World Health Organ Tech Rep Ser. 2007;(935):1-265, back cover
18330140
EMBO J. 1996 Aug 15;15(16):4317-29
8861960
Eur J Cell Biol. 1999 Feb;78(2):79-90
10099930
Genes Dev. 1989 Oct;3(10):1613-24
2612907
FEBS Lett. 1998 Nov 6;438(3):165-70
9827539
Int J Biochem Cell Biol. 2009 Oct;41(10):2051-61
19703661
Nat Genet. 2002 Sep;32(1):128-34
12185368
Development. 2006 Nov;133(22):4439-50
17075007
Nat Genet. 2000 Jan;24(1):75-8
10615132
EMBO J. 1984 Jul;3(7):1521-4
6204864
Sci STKE. 2006 Dec 05;2006(364):cm7
17148788
Science. 2009 Jun 26;324(5935):1707-10
19556507
Mol Cell Biol. 1989 Jun;9(6):2464-76
2788241
Pancreas. 1995 May;10(4):389-94
7792296
Nat Genet. 2004 Dec;36(12):1301-5
15543146
Am J Physiol Cell Physiol. 2005 Nov;289(5):C1169-78
15987769
Hepatology. 2003 Dec;38(6):1331-47
14647040
Mol Cell Biol. 2008 Sep;28(17):5458-68
18606784
Curr Biol. 2003 Jan 21;13(2):105-15
12546783
J Biol Chem. 2001 Nov 23;276(47):44018-26
11562365
Biochem Biophys Res Commun. 1990 Jan 15;166(1):358-64
1689152
Genome Biol. 2002;3(5):research0023
12049664
J Cell Physiol. 1968 Oct;72(2):Suppl 1:1-18
5693298
Differentiation. 2009 Jan;77(1):48-59
19281764
J Biol Chem. 1977 Oct 25;252(20):7391-7
903366
Nat Methods. 2008 Jul;5(7):621-8
18516045
Genome Res. 2002 Apr;12(4):656-64
11932250
Am J Physiol Gastrointest Liver Physiol. 2008 Mar;294(3):G717-27
18202109
Mol Cell Biol. 2006 Jan;26(1):117-30
16354684
Mol Cell Biol. 1997 May;17(5):2679-87
9111338
FEBS Lett. 1975 Jul 15;55(1):91-3
1140432
Hum Mol Genet. 1997 Jun;6(6):897-903
9175736
Nat Cell Biol. 2000 Dec;2(12):879-87
11146651
J Biol Chem. 1981 Dec 10;256(23):12367-73
7028754
J Cell Biol. 1980 Sep;86(3):784-94
7410479
Diabetologia. 2004 Apr;47(4):597-613
15298336
Genes Dev. 1998 Dec 1;12(23):3752-63
9851981