Pancreatic inactivation of c-Myc decreases acinar mass and transdifferentiates acinar cells into adipocytes in mice.
OBJECTIVE
The pancreatic mass is determined by the coordinated expansion and differentiation of progenitor cells and is maintained via tight control of cell replacement rates. The basic helix-loop-helix transcription factor c-Myc is one of the main regulators of these processes in many organs. We studied the requirement of c-Myc in controlling the generation and maintenance of pancreatic mass.


METHODS
We conditionally inactivated c-Myc in Pdx1+ pancreatic progenitor cells. Pancreata of mice lacking c-Myc (c-Myc(P-/-) mice) were analyzed during development and ageing.


RESULTS
Pancreatic growth in c-Myc(P-/-) mice was impaired starting on E12.5, in early primordia, because of decreased proliferation and altered differentiation of exocrine progenitors; islet progenitors were spared. Acinar cell maturation was defective in the adult hypotrophic pancreas, which hampered exocrine mass maintenance in aged animals. From 2 to 10 months of age, the c-Myc(P-/-) pancreas was progressively remodeled without inflammatory injury. Loss of acinar cells increased with time, concomitantly with adipose tissue accumulation. Using a genetic cell lineage tracing analysis, we demonstrated that pancreatic adipose cells were derived directly from transdifferentiating acinar cells. This epithelial-to-mesenchyme transition was also observed in normal aged specimens and in pancreatitis.


CONCLUSIONS
These results provide evidence indicating that c-Myc activity is required for growth and maturation of the exocrine pancreas, and sheds new light on the ontogeny of pancreatic adipose cells in processes of organ degenerescence and tissue involution.
Bonal
Claire
C
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
Thorel
Fabrizio
F
Ait-Lounis
Aouatef
A
Reith
Walter
W
Trumpp
Andreas
A
Herrera
Pedro L
PL
D017667:Adipocytes / Q000166:cytology*; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D004848:Epithelium / Q000473:pathology; D018398:Homeodomain Proteins / Q000032:analysis; D006801:Humans; D008648:Mesoderm / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D046790:Pancreas, Exocrine / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis / Q000502:physiology*; D015534:Trans-Activators / Q000032:analysis
D018398:Homeodomain Proteins; C489427:MYC protein, human; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein