Notch/Rbp-j signaling prevents premature endocrine and ductal cell differentiation in the pancreas.
To investigate the precise role of Notch/Rbp-j signaling in the pancreas, we inactivated Rbp-j by crossing Rbp-j floxed mice with Pdx.cre or Rip.cre transgenic mice. The loss of Rbp-j at the initial stage of pancreatic development induced accelerated alpha and PP cell differentiation and a concomitant decrease in the number of Neurogenin3 (Ngn3)-positive cells at E11.5. Then at E15, elongated tubular structures expressing ductal cell markers were evident; however, differentiation of acinar and all types of endocrine cells were reduced. During later embryonic stages, compensatory acinar cell differentiation was observed. The resultant mice exhibited insulin-deficient diabetes with both endocrine and exocrine pancreatic hypoplasia. In contrast, the loss of Rbp-j specifically in beta cells did not affect beta cell number and function. Thus, our analyses indicate that Notch/Rbp-j signaling prevents premature differentiation of pancreatic progenitor cells into endocrine and ductal cells during early development of the pancreas.
Fujikura
Junji
J
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Hosoda
Kiminori
K
Iwakura
Hiroshi
H
Tomita
Tsutomu
T
Noguchi
Michio
M
Masuzaki
Hiroaki
H
Tanigaki
Kenji
K
Yabe
Daisuke
D
Honjo
Tasuku
T
Nakao
Kazuwa
K
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007328:Insulin / Q000172:deficiency; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010183:Pancreatic Ducts / Q000166:cytology / Q000196:embryology* / Q000378:metabolism* / Q000473:pathology; D051880:Receptors, Notch / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells
D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D007328:Insulin; C497571:Rbpj protein, mouse; D051880:Receptors, Notch