Mesenchymal Bone Morphogenetic Protein Signaling Is Required for Normal Pancreas Development

Hagedorn Research Institute, Gentofte, Denmark.
Diabetes (Impact Factor: 8.1). 08/2010; 59(8):1948-56. DOI: 10.2337/db09-1010
Source: PubMed


Pancreas organogenesis is orchestrated by interactions between the epithelium and the mesenchyme, but these interactions are not completely understood. Here we investigated a role for bone morphogenetic protein (BMP) signaling within the pancreas mesenchyme and found it to be required for the normal development of the mesenchyme as well as for the pancreatic epithelium.
We analyzed active BMP signaling by immunostaining for phospho-Smad1,5,8 and tested whether pancreas development was affected by BMP inhibition after expression of Noggin and dominant negative BMP receptors in chicken and mouse pancreas.
Endogenous BMP signaling is confined to the mesenchyme in the early pancreas and inhibition of BMP signaling results in severe pancreatic hypoplasia with reduced epithelial branching. Notably, we also observed an excessive endocrine differentiation when mesenchymal BMP signaling is blocked, presumably secondary to defective mesenchyme to epithelium signaling.
We conclude that BMP signaling plays a previously unsuspected role in the mesenchyme, required for normal development of the mesenchyme as well as for the epithelium.

Download full-text


Available from: Philippe Ravassard, Sep 17, 2014
12 Reads
  • Source
    • "Bone morphogenetic protein (BMP) 2, a member of the TGF-β superfamily, has been implicated in the development of the skeleton, kidney and pancreas [13]–[15]. It functions by binding to the type II receptor (BMPR2) and recruiting a type I receptor (BMPR1a, BMPR1b or ACVR1), then phosphorylating intracellular substrates, i.e., Smad1, Smad5, and Smad8, which form complex with Smad4, translocate into the nucleus and regulate the transcription of various targets [16]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Bone morphogenetic proteins (BMPs) have an anti-fibrogenic function in the kidney, lung, and liver. However, their role in chronic pancreatitis (CP) is unknown. The aim of this study was to define the anti-fibrogenic role of BMP signaling in the pancreas in vivo under CP induction. Mice with a deletion of BMP type II receptor (BMPR2(+/-)) were used in this study in comparison with wild-type mice. CP was induced by repetitive cerulein injection intraperitoneally for 4 weeks, and the severity of CP was evaluated. Pancreatic stellate cells (PSCs) were isolated from the mice and treated with BMP2 and TGF-β in vitro, and extracellular matrix protein (ECM) production was measured. Smad and mitogen-activated protein kinase (MAPK) signaling was also evaluated. BMPR2(+/-) mice revealed a greater pancreatic fibrosis, PSC activation and leukocyte infiltration after CP induction compared to wild-type mice (P<0.05). Under CP induction, phospho (p)Smad1/5/8 was elevated in wild-type mice and this effect was abolished in BMPR2(+/-) mice; pSmad2 and pp38(MAPK) were further enhanced in BMPR2(+/-) mice compared to wild-type mice (P<0.05). In vitro, BMP2 inhibited TGF-β-induced ECM protein fibronectin production in wild-type PSCs; this effect was abolished in BMPR2(+/-) PSCs (P<0.05). In BMPR2(+/-) PSCs, pSmad1/5/8 level was barely detectable upon BMP2 stimulation, while pSmad2 level was further enhanced by TGF-β stimulation, compared to wild-type PSCs (P<0.05). BMPR2/Smad1/5/8 signaling plays a protective role against cerulein-induced pancreatic fibrosis by inhibiting Smad2 and p38(MAPK) signaling pathways.
    PLoS ONE 02/2014; 9(2):e89114. DOI:10.1371/journal.pone.0089114 · 3.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Embryonic development marks a period of peak tissue growth and morphogenesis in the mammalian lifecycle. Many of the pathways that underlie cell proliferation and movement are relatively quiescent in adult animals but become reactivated during carcinogenesis. This phenomenon has been particularly well documented in pancreatic cancer, where detailed genetic studies and a robust mouse model have permitted investigators to test the role of various developmental signals in cancer progression. In this chapter, we review current knowledge regarding the signaling pathways that act during pancreatic development and the evidence that the reactivation of developmentally important signals is critical for the pathogenesis of this treatment-refractory malignancy.
    Progress in molecular biology and translational science 01/2010; 97:41-78. DOI:10.1016/B978-0-12-385233-5.00002-7 · 3.49 Impact Factor
  • Source
    Diabetes 02/2011; 60(2):364-76. DOI:10.2337/db10-1068 · 8.10 Impact Factor
Show more