Elucidation fo molecular mechanism of pancreatic befa ceel differentiation using fissue-specific koock-out mice for the regeneration of beta ceas

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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 dfferentiation 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 bete cell number and function.We also generated mice in which the Rbp-j gene was inactivated in Ptfla-expressing cells using Ptfla.cre mice. The timing of the Cre-mediated deletion in Rbp-j(f/f) Ptfla.cre mice is 1 day later than that in Rbp-j(f/f) Pdx.cre mice. In Rbp-j(f/f) Ptfla.cre mouse pancreases, at E13.5, the reduced Hesl expression was accompanied by reduced epithelial growth, but premature endocrine cell differentiation was minimal. At E15.5, Pdxl expression was repressed and acinar cell differentiation was reduced, but an increase in acinar cell proliferation was observed during the per natal period. 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.Our study indicates that in addition to its role in preventing premature differentiation of early endocrine cells, Rbp-j regulates epithelial growth, Pdxl expression, and acinar cell differentiation during mid-pancreatic development.