Jagged1 is a competitive inhibitor of Notch signaling in the embryonic pancreas

Department of Genetics, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Mechanisms of development (Impact Factor: 2.24). 07/2009; 126(8-9):687-99. DOI: 10.1016/j.mod.2009.05.005
Source: PubMed

ABSTRACT Pancreatic endocrine cells originate from precursors that express the transcription factor Neurogenin3 (Ngn3). Ngn3 expression is repressed by active Notch signaling. Accordingly, mice with Notch signaling pathway mutations display increased Ngn3 expression and endocrine cell lineage allocation. To determine how the Notch ligand Jagged1 (Jag1) functions during pancreas development, we deleted Jag1 in foregut endoderm and examined postnatal and embryonic endocrine cells and precursors. Postnatal Jag1 mutants display increased Ngn3 expression, alpha-cell mass, and endocrine cell percentage, similar to the early embryonic phenotype of Dll1 and Rbpj mutants. However, in sharp contrast to postnatal animals, Jag1-deficient embryos display increased expression of Notch transcriptional targets and decreased Ngn3 expression, resulting in reduced endocrine lineage allocation. Jag1 acts as an inhibitor of Notch signaling during embryonic pancreas development but an activator of Notch signaling postnatally. Expression of the Notch modifier Manic Fringe (Mfng) is limited to endocrine precursors, providing a possible explanation for the inhibition of Notch signaling by Jag1 during mid-gestation embryonic pancreas development.

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    • "RESEARCH ARTICLE Development (2014) 141, 2313-2324 doi:10.1242/dev.108100 DEVELOPMENT has been shown also in the lens (Le et al., 2009), developing pancreas (Golson et al., 2009), early hematopoiesis (Robert-Moreno et al., 2008) and angiogenesis (Benedito et al., 2009). However, this correspondence does not seem to hold for all situations; for example, Jag1 selects V1 neuroblasts in the neural tube by lateral inhibition (Ramos et al., 2010). "
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    ABSTRACT: During inner ear development, Notch exhibits two modes of operation: lateral induction, which is associated with prosensory specification, and lateral inhibition, which is involved in hair cell determination. These mechanisms depend respectively on two different ligands, jagged 1 (Jag1) and delta 1 (Dl1), that rely on a common signaling cascade initiated after Notch activation. In the chicken otocyst, expression of Jag1 and the Notch target Hey1 correlates well with lateral induction, whereas both Jag1 and Dl1 are expressed during lateral inhibition, as are Notch targets Hey1 and Hes5. Here, we show that Jag1 drives lower levels of Notch activity than Dl1, which results in the differential expression of Hey1 and Hes5. In addition, Jag1 interferes with the ability of Dl1 to elicit high levels of Notch activity. Modeling the sensory epithelium when the two ligands are expressed together shows that ligand regulation, differential signaling strength and ligand competition are crucial to allow the two modes of operation and for establishing the alternate pattern of hair cells and supporting cells. Jag1, while driving lateral induction on its own, facilitates patterning by lateral inhibition in the presence of Dl1. This novel behavior emerges from Jag1 acting as a competitive inhibitor of Dl1 for Notch signaling. Both modeling and experiments show that hair cell patterning is very robust. The model suggests that autoactivation of proneural factor Atoh1, upstream of Dl1, is a fundamental component for robustness. The results stress the importance of the levels of Notch signaling and ligand competition for Notch function.
    Development 05/2014; 141(11). DOI:10.1242/dev.108100 · 6.27 Impact Factor
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    • "Given recent reports that Jagged1 inhibits Notch signaling during early pancreas morphogenesis (Golson et al., 2009) and in developing blood vessels (Benedito et al., 2009), it is possible that lateral inhibition in the pancreas is mediated by downregulation of inhibitory Jagged1 expression in Ngn3 + cells, permitting activation of Notch signaling in adjacent cells through other Delta-family ligands whose level of expression need not change (model, Fig. 7). In support of this model, the expression of Manic Fringe, which is essential for the inhibitory effect of Jagged at the receiving cell, is restricted to Ngn3 + cells (Golson et al., 2009; Svensson et al., 2009; Xu et al., 2006). Thus, the control of Jagged1 and Manic Fringe expression by Ngn3 could be the basis for the lateral interactions controlling endocrine and tip fates. "
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