Complex regulation controls Neurogenin3 proteolysis

Roark, R. C.; Itzhaki, Laura S.; Philpott, Anna

doi:10.1242/bio.20121750

Cited by 34 publications

(34 citation statements)

References 33 publications

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“…Ngn3-hemagglutinin (Ngn3-HA) coimmunoprecipitated Flag-tagged Fbw7 isoform-α and, to a lesser extent, isoform-β (Figure 4B, left panel; and vice versa, as shown in the right panel), and endogenous Fbw7 interacted with Ngn3-HA (Figure 4C). Ngn3 is a heavily ubiquitinated protein (Roark et al., 2012), but Ngn3 ubiquitination was strongly reduced in Fbw7 Δ HCT116 cells when compared to congenic Fbw7 wt cells (Figure 4D). In vitro, wild-type (WT) Fbw7–Flag protein complexes promoted efficient ubiquitination of recombinant Ngn3, but the inactive mutant Fbw7α-ΔFbox–Flag did not (Welcker et al., 2004) (Figures 4E and S4A).…”

Section: Resultsmentioning

confidence: 99%

Loss of Fbw7 Reprograms Adult Pancreatic Ductal Cells into α, δ, and β Cells

et al. 2014

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SummaryThe adult pancreas is capable of limited regeneration after injury but has no defined stem cell population. The cell types and molecular signals that govern the production of new pancreatic tissue are not well understood. Here, we show that inactivation of the SCF-type E3 ubiquitin ligase substrate recognition component Fbw7 induces pancreatic ductal cells to reprogram into α, δ, and β cells. Loss of Fbw7 stabilized the transcription factor Ngn3, a key regulator of endocrine cell differentiation. The induced β cells resemble islet β cells in morphology and histology, express genes essential for β cell function, and release insulin after glucose challenge. Thus, loss of Fbw7 appears to reawaken an endocrine developmental differentiation program in adult pancreatic ductal cells. Our study highlights the plasticity of seemingly differentiated adult cells, identifies Fbw7 as a master regulator of cell fate decisions in the pancreas, and reveals adult pancreatic duct cells as a latent multipotent cell type.

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Section: Resultsmentioning

confidence: 99%

Loss of Fbw7 Reprograms Adult Pancreatic Ductal Cells into α, δ, and β Cells

et al. 2014

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“…Id regulates E in diverse developmental and physiological processes, and how it regulates E continues to be investigated (Ling et al 2014;Miyazaki et al 2015). In addition, in some contexts, E proteins may stabilize their dimerization partners (Viñals et al 2004;Roark et al 2012). In this study, we made the novel observation that dimer formation can instead promote bHLH protein instability.…”

mentioning

confidence: 84%

Dimerization-driven degradation of C. elegans and human E proteins

Sallee

Greenwald

2015

Genes Dev.

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E proteins are conserved regulators of growth and development. We show that the Caenorhabditis elegans E-protein helix-loop-helix-2 (HLH-2) functions as a homodimer in directing development and function of the anchor cell (AC) of the gonad, the critical organizer of uterine and vulval development. Our structure-function analysis of HLH-2 indicates that dimerization drives its degradation in other uterine cells (ventral uterine precursor cells [VUs]) that initially have potential to be the AC. We also provide evidence that this mode of dimerization-driven down-regulation can target other basic HLH (bHLH) dimers as well. Remarkably, human E proteins can functionally substitute for C. elegans HLH-2 in regulating AC development and also display dimerizationdependent degradation in VUs. Our results suggest that dimerization-driven regulation of bHLH protein stability may be a conserved mechanism for differential regulation in specific cell contexts.

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“…Neurog3 has been shown to be inherently unstable and subject to the same ubiquitylation-mediated degradation mechanisms as Neurog2 (Roark et al 2012;Qu et al 2013). These striking parallels for Neurog2 and Neurog3 predict that low levels of unstable Neurog3 activate a subset of target genes specifically associated with promoting progenitor maintenance and the endocrine-biased state.…”

Section: In Our Neurog3mentioning

confidence: 99%

“…4; Supplemental Table S3). Moreover, enforcing G1-like conditions with the Cdki p27Kip1 led to significantly increased Neurog3 stability (Roark et al 2012). In the Neurog3 HI state, Neurog3 promotes expression of the Cdki Cdkn1a (Miyatsuka et al 2011), confirmed by our qRT-PCR analysis, creating a positive feed-forward loop driving cell cycle exit.…”

Section: In Our Neurog3mentioning

confidence: 99%

Precommitment low-level Neurog3 expression defines a long-lived mitotic endocrine-biased progenitor pool that drives production of endocrine-committed cells

et al. 2016

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+ 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 Neurog3TA.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 + Neurog3TA.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.[Keywords: Neurog3; progenitor; endocrine-biased; mitotic] Supplemental material is available for this article. During mammalian organogenesis, lineage specification and commitment involve passage through distinct progenitor/precursor states that rely on different combinations and levels of transcription factors (Wilkinson et al. 2013;Cano et al. 2014). In the current model of pancreatic endocrine cell formation, Neurogenin3 (Neurog3) expression in the epithelium rapidly progresses to a high-level production of protein (Neurog3 HI ) that leads to endocrine fate commitment, cell cycle exit, and delamination toward proto-islet clusters. Meta-analysis of published literature (see below), however, is suggestive of a broader pattern of lower-level Neurog3 expression across the epithelium that is substantially more prevalent than the actively delaminating endocrine-committed Neurog3 HI population. The present study is focused on determining whether this low-Neurog3-expressing subpopulation represents the early-phase expression in post-mitotic cells on their way to becoming Neurog3 HI cells or endocrine fate-biased but uncommitted mitotic cells that have self-maintaining progenitor characteristics.Pancreas organogenesis is divided into a primary transition and secondary transition (Pan and Wright 2011). During the primary transition (embryonic day 9.5 [E9.5] to E12.5), multipotent progenitor cells undergo apical polarization, forming microlumens that then coalesce to generate an epithelial plexus. Within this epithelial plexus, progenitor cells (around E12.5) segregate into "tip" and "trunk" domains. In the short-term, tip domains

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Complex regulation controls Neurogenin3 proteolysis

Cited by 34 publications

References 33 publications

Loss of Fbw7 Reprograms Adult Pancreatic Ductal Cells into α, δ, and β Cells

Loss of Fbw7 Reprograms Adult Pancreatic Ductal Cells into α, δ, and β Cells

Dimerization-driven degradation of C. elegans and human E proteins

Precommitment low-level Neurog3 expression defines a long-lived mitotic endocrine-biased progenitor pool that drives production of endocrine-committed cells

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