Bmp2 Signaling Regulates the Hepatic versus Pancreatic Fate Decision

Department of Biochemistry and Biophysics, Programs in Developmental Biology, Genetics and Human Genetics, University of California, San Francisco, 1550 4th Street, San Francisco, CA 94158, USA.
Developmental Cell (Impact Factor: 9.71). 12/2008; 15(5):738-48. DOI: 10.1016/j.devcel.2008.08.019
Source: PubMed


Explant culture data have suggested that the liver and pancreas originate from common progenitors. We used single-cell-lineage tracing in zebrafish to investigate this question in vivo as well as to analyze the hepatic versus pancreatic fate decision. At early somite stages, endodermal cells located at least two cells away from the midline can give rise to both liver and pancreas. In contrast, endodermal cells closer to the midline give rise to pancreas and intestine, but not liver. Loss- and gain-of-function analyses show that Bmp2b, expressed in the lateral plate mesoderm, signals through Alk8 to induce endodermal cells to become liver. When Bmp2b was overexpressed, medially located endodermal cells, fated to become pancreas and intestine, contributed to the liver. These data provide in vivo evidence for the existence of bipotential hepatopancreatic progenitors and indicate that their fate is regulated by the medio-lateral patterning of the endodermal sheet, a process controlled by Bmp2b.

Download full-text


Available from: Won-Suk Chung,
18 Reads
  • Source
    • "Although these studies map bipotential progenitors and the timing of their segregation into a liver or pancreas anlagen, it is thought that the fates of these segregated populations might be reversible in early somite stages such that modulation of extrinsic signals can shift one fate into another (Miki et al., 2012). In zebrafish, endodermal cells capable of both a liver and exocrine pancreas fate have been identified at the six-to eight-somite stage (Chung et al., 2008). Although these labeling studies localize bipotential progenitors, how this population spatially relates to multiple signals that regulate liver versus pancreas specification is poorly understood. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The liver and pancreas arise from common endodermal progenitors. How these distinct cell fates are specified is poorly understood. Here we describe prostaglandin E2 (PGE2) as a regulator of endodermal fate specification during development. Modulating PGE2 activity has opposing effects on liver versus pancreas specification in zebrafish embryos as well as mouse endodermal progenitors. The PGE2 synthetic enzyme cox2a and receptor ep2a are patterned such that cells closest to PGE2 synthesis acquire a liver fate, whereas more distant cells acquire a pancreas fate. PGE2 interacts with the bmp2b pathway to regulate fate specification. At later stages of development, PGE2 acting via the ep4a receptor promotes outgrowth of both the liver and pancreas. PGE2 remains important for adult organ growth, as it modulates liver regeneration. This work provides in vivo evidence that PGE2 may act as a morphogen to regulate cell-fate decisions and outgrowth of the embryonic endodermal anlagen.
    Developmental Cell 02/2014; 28(4). DOI:10.1016/j.devcel.2014.01.006 · 9.71 Impact Factor
  • Source
    • "Together, these results indicate a key role for GR signaling in the regulation of BMP-mediated functions and BMP-responsive genes during zebrafish embryogenesis. BMP signaling regulates a variety of important developmental processes, including dorsoventral patterning and initial mesodermal differentiation [9,25], as well as later morphogenic developments such as angiogenesis, myogenesis, and organogenesis [13,15]. These results lead us to hypothesize that cortisol and glucocorticoid receptor transcripts transferred from the mother may be essential for early patterning and developmental cell fate determinations, and the mechanism of action may involve modulation of BMP signaling. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cortisol is the primary corticosteroid in teleosts that is released in response to stressor activation of the hypothalamus-pituitary-interrenal axis. The target tissue action of this hormone is primarily mediated by the intracellular glucocorticoid receptor (GR), a ligand-bound transcription factor. In developing zebrafish (Danio rerio) embryos, GR transcripts and cortisol are maternally deposited into the oocyte prior to fertilization and influence early embryogenesis. To better understand of the molecular mechanisms involved, we investigated changes in the developmental transcriptome prior to hatch, in response to morpholino oligonucleotide knockdown of GR using the Agilent zebrafish microarray platform. A total of 1313 and 836 mRNA transcripts were significantly changed at 24 and 36 hours post fertilization (hpf), respectively. Functional analysis revealed numerous developmental processes under GR regulation, including neurogenesis, eye development, skeletal and cardiac muscle formation. Together, this study underscores a critical role for glucocorticoid signaling in programming molecular events essential for zebrafish development.
    PLoS ONE 11/2013; 8(11):e80726. DOI:10.1371/journal.pone.0080726 · 3.23 Impact Factor
  • Source
    • "For gene and primer information, including accession numbers, refer to Supporting Table S2. For confocal microscopy, outcrossed Tg(Xla.Eef1a1:GFP)s854 embryos [hereafter referred to as gutGFP] were injected as above and processed as previously published [47]. Images were acquired on a Zeiss LSM700 confocal microscope and analyzed with ImageJ (US National Institutes of Health). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sfrp5 belongs to the family of secreted frizzled related proteins (Sfrp), secreted inhibitors of Wingless-MMTV Integration Site (Wnt) signaling, which play an important role in cancer and development. We selected sfrp5 because of its compelling expression profile in the developing endoderm in zebrafish, Danio rerio. In this study, overexpression of sfrp5 in embryos results in defects in both convergent extension (CE) by inhibition of non-canonical Wnt signaling and defects in dorsoventral patterning by inhibition of Tolloid-mediated proteolysis of the BMP inhibitor Chordin. From 25 hours post fertilization (hpf) to 3 days post fertilization (dpf), both overexpression and knockdown of Sfrp5 decrease the size of the endoderm, significantly reducing liver cell number. At 3 dpf, insulin-positive endodermal cells fail to coalesce into a single pancreatic islet. We show that Sfrp5 inhibits both canonical and non-canonical Wnt signaling during embryonic and endodermal development, resulting in endodermal abnormalities.
    PLoS ONE 09/2013; 8(4):e62470. DOI:10.1371/journal.pone.0062470 · 3.23 Impact Factor
Show more