Beta-cell proliferation, but not neogenesis, following 60% partial pancreatectomy is impaired in the absence of FoxM1.
OBJECTIVE
This study was designed to determine whether the transcription factor FoxM1 was required for regeneration of beta-cell mass via proliferation and/or neogenesis in the adult after 60% partial pancreatectomy (PPx).


METHODS
Adult mice with a pancreas-wide deletion of Foxm1 (Foxm1(flox/flox);Pdx1-Cre [FoxM1(Deltapanc)]) and their control littermates (Foxm1(flox/flox)) were subjected to PPx or a sham operation, after which islet expression of Foxm1 and several target genes, beta-cell mass, proliferation, beta-cell size, islet size, islet density, and neurogenin-3 expression were analyzed.


RESULTS
In control mice, PPx stimulated beta-cell proliferation and neogenesis and upregulated Foxm1 and several of its known targets (Plk1, Cenp-a, Birc5/Survivin, and Ccnb1) in islets. Within 1 week post-PPx, control mice underwent significant regeneration of beta-cell mass, and average islet size within the regenerating lobe was similar to that after a sham operation. However, FoxM1(Deltapanc) mice exhibited specific impairments in beta-cell mass regeneration and islet growth after PPx, with reduced proliferation of alpha- and beta-cells but no impairments in acinar or ductal cell proliferation. Interestingly, FoxM1 was not required for proliferation of beta-cells within small endocrine cell clusters located in the regenerating portion of the pancreas but was specifically required for proliferation of beta-cells within larger islets. Additionally, FoxM1 was not required for beta-cell neogenesis following PPx.


CONCLUSIONS
Our results indicate that FoxM1 is partially required for increased beta-cell proliferation, but not beta-cell neogenesis, stimulated by PPx. Furthermore, FoxM1 seems to be dispensable for proliferation of beta-cells following neogenesis but is required for proliferation of preexisting beta-cells.
Ackermann Misfeldt
Amanda
A
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Costa
Robert H
RH
Gannon
Maureen
M
D000818:Animals; D053145:Cell Nucleus Size; D049109:Cell Proliferation; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010180:Pancreatectomy / Q000009:adverse effects / Q000379:methods*
D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse