The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells.
We have previously reported that the loss of Arx and/or Pax4 gene activity leads to a shift in the fate of the different endocrine cell subtypes in the mouse pancreas, without affecting the total endocrine cell numbers. Here, we conditionally and ectopically express Pax4 using different cell-specific promoters and demonstrate that Pax4 forces endocrine precursor cells, as well as mature alpha cells, to adopt a beta cell destiny. This results in a glucagon deficiency that provokes a compensatory and continuous glucagon+ cell neogenesis requiring the re-expression of the proendocrine gene Ngn3. However, the newly formed alpha cells fail to correct the hypoglucagonemia since they subsequently acquire a beta cell phenotype upon Pax4 ectopic expression. Notably, this cycle of neogenesis and redifferentiation caused by ectopic expression of Pax4 in alpha cells is capable of restoring a functional beta cell mass and curing diabetes in animals that have been chemically depleted of beta cells.
Collombat
Patrick
P
Department of Molecular Cell Biology, Max-Planck Institute for Biophysical Chemistry, Am Fassberg, D-37077 Göttingen, Germany. collombat@unice.fr
Xu
Xiaobo
X
Ravassard
Philippe
P
Sosa-Pineda
Beatriz
B
Dussaud
Sébastien
S
Billestrup
Nils
N
Madsen
Ole D
OD
Serup
Palle
P
Heimberg
Harry
H
Mansouri
Ahmed
A
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D005934:Glucagon / Q000172:deficiency; D050416:Glucagon-Secreting Cells / Q000166:cytology*; D018398:Homeodomain Proteins / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology*; D007515:Islets of Langerhans / Q000166:cytology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D051761:Paired Box Transcription Factors / Q000378:metabolism*; D010179:Pancreas / Q000166:cytology* / Q000254:growth & development; D013234:Stem Cells / Q000166:cytology*
D051792:Basic Helix-Loop-Helix Proteins; D005934:Glucagon; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D051761:Paired Box Transcription Factors; C407737:Neurog3 protein, mouse; C110218:Pax4 protein, mouse