The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells

TY - JOUR

T1 - The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells

AU - Collombat, Patrick

AU - Xu, Xiaobo

AU - Ravassard, Philippe

AU - Sosa-Pineda, Beatriz

AU - Dussaud, Sébastien

AU - Billestrup, Nils

AU - Madsen, Ole D.

AU - Serup, Palle

AU - Heimberg, Harry

AU - Mansouri, Ahmed

N1 - Keywords: Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Differentiation; Diabetes Mellitus, Experimental; Glucagon; Glucagon-Secreting Cells; Homeodomain Proteins; Insulin-Secreting Cells; Islets of Langerhans; Mice; Nerve Tissue Proteins; Paired Box Transcription Factors; Pancreas; Stem Cells

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

U2 - 10.1016/j.cell.2009.05.035

DO - 10.1016/j.cell.2009.05.035

M3 - Journal article

C2 - 19665969

SN - 0092-8674

VL - 138

SP - 449

EP - 462

JO - Cell

JF - Cell

IS - 3

ER -