title: Precommitment low-level Neurog3 expression defines a long-lived mitotic endocrine-biased progenitor pool that drives production of endocrine-committed cells.
abstract: The current model for endocrine cell specification in the pancreas invokes high-level production of the transcription factor Neurogenin 3 (Neurog3) in Sox9(+) bipotent epithelial cells as the trigger for endocrine commitment, cell cycle exit, and rapid delamination toward proto-islet clusters. This model posits a transient Neurog3 expression state and short epithelial residence period. We show, however, that a Neurog3(TA.LO) cell population, defined as Neurog3 transcriptionally active and Sox9(+) and often containing nonimmunodetectable Neurog3 protein, has a relatively high mitotic index and prolonged epithelial residency. We propose that this endocrine-biased mitotic progenitor state is functionally separated from a pro-ductal pool and endows them with long-term capacity to make endocrine fate-directed progeny. A novel BAC transgenic Neurog3 reporter detected two types of mitotic behavior in Sox9(+) Neurog3(TA.LO) progenitors, associated with progenitor pool maintenance or derivation of endocrine-committed Neurog3(HI) cells, respectively. Moreover, limiting Neurog3 expression dramatically increased the proportional representation of Sox9(+) Neurog3(TA.LO) progenitors, with a doubling of its mitotic index relative to normal Neurog3 expression, suggesting that low Neurog3 expression is a defining feature of this cycling endocrine-biased state. We propose that Sox9(+) Neurog3(TA.LO) endocrine-biased progenitors feed production of Neurog3(HI) endocrine-committed cells during pancreas organogenesis.
authors: Vanderbilt University Program in Developmental Biology, Department of Cell and Developmental Biology, Vanderbilt Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA;
authors: Matthew E
authors: ME
authors: Bechard
authors: Vanderbilt University Program in Developmental Biology, Department of Cell and Developmental Biology, Vanderbilt Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA;
authors: Eric D
authors: ED
authors: Bankaitis
authors: Vanderbilt University Program in Developmental Biology, Department of Cell and Developmental Biology, Vanderbilt Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors: Susan B
authors: SB
authors: Hipkens
authors: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors: Alessandro
authors: A
authors: Ustione
authors: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors: David W
authors: DW
authors: Piston
authors: Vanderbilt University Program in Developmental Biology, Department of Cell and Developmental Biology, Vanderbilt Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA;
authors: Yu-Ping
authors: YP
authors: Yang
authors: Vanderbilt University Program in Developmental Biology, Department of Cell and Developmental Biology, Vanderbilt Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors: Mark A
authors: MA
authors: Magnuson
authors: Vanderbilt University Program in Developmental Biology, Department of Cell and Developmental Biology, Vanderbilt Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA;
authors: Christopher V E
authors: CV
authors: Wright
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000235:genetics; D055098:Endocrine Cells / Q000166:cytology*; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008938:Mitosis; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D010179:Pancreas / Q000166:cytology; D013234:Stem Cells / Q000166:cytology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; C407737:Neurog3 protein, mouse
keywords: Neurog3; endocrine-biased; mitotic; progenitor