The phosphorylation status of Ascl1 is a key determinant of neuronal differentiation and maturation <i>in vivo</i> and <i>in vitro</i>

Ali, Fahad; Cheng, Kevin; Kirwan, Peter; Metcalfe, Su; Livesey, Frederick J.; Barker, Roger A.; Philpott, Anna

doi:10.1242/dev.106377

Cited by 78 publications

(143 citation statements)

References 30 publications

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“…Both Ascl1 and Ngn2 are heavily phosphorylated by, among others, GSK3 and Cdks (50–53). Cdk phosphorylation downregulates the biological activity of Ascl1 and Ngn2, consistent with the fact that cell cycle prolongation is needed to promote neuronal differentiation in vertebrates (50,51). GSK3 phosphorylation of Ngn2, on the other hand, is thought to affect the binding specificity to differential subsets of downstream targets (53,54).…”

Section: Introductionsupporting

confidence: 61%

bHLH proteins involved in Drosophila neurogenesis are mutually regulated at the level of stability

Kiparaki

Zarifi

Delidakis

2015

Nucleic Acids Research

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Proneural bHLH activators are expressed in all neuroectodermal regions prefiguring events of central and peripheral neurogenesis. Drosophila Sc is a prototypical proneural activator that heterodimerizes with the E-protein Daughterless (Da) and is antagonized by, among others, the E(spl) repressors. We determined parameters that regulate Sc stability in Drosophila S2 cells. We found that Sc is a very labile phosphoprotein and its turnover takes place via at least three proteasome-dependent mechanisms. (i) When Sc is in excess of Da, its degradation is promoted via its transactivation domain (TAD). (ii) In a DNA-bound Da/Sc heterodimer, Sc degradation is promoted via an SPTSS phosphorylation motif and the AD1 TAD of Da; Da is spared in the process. (iii) When E(spl)m7 is expressed, it complexes with Sc or Da/Sc and promotes their degradation in a manner that requires the corepressor Groucho and the Sc SPTSS motif. Da/Sc reciprocally promotes E(spl)m7 degradation. Since E(spl)m7 is a direct target of Notch, the mutual destabilization of Sc and E(spl) may contribute in part to the highly conserved anti-neural activity of Notch. Sc variants lacking the SPTSS motif are dramatically stabilized and are hyperactive in transgenic flies. Our results propose a novel mechanism of regulation of neurogenesis, involving the stability of key players in the process.

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Section: Introductionsupporting

confidence: 61%

bHLH proteins involved in Drosophila neurogenesis are mutually regulated at the level of stability

Kiparaki

Zarifi

Delidakis

2015

Nucleic Acids Research

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“…PNECs have properties of both endocrine and neuronal cells. They express neuronal markers, such as neural cell adhesion molecule (NCAM1) and ASCL1, a key determinant of neuronal fate specification (Linnoila 2006;Ali et al 2014;Chanda et al 2014). In addition, NEBs are associated with intraepithelial nerve fibers and can transmit signals to the CNS.…”

Section: Respiratory Lineage Specification and Functionmentioning

confidence: 99%

Origins, genetic landscape, and emerging therapies of small cell lung cancer

2015

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Lung cancer is the leading cause of cancer deaths, with small cell lung cancer (SCLC) representing the most aggressive subtype. Standard treatments have not changed in decades, and the 5-year survival rate has remained <7%. Genomic analyses have identified key driver mutations of SCLC that were subsequently validated in animal models of SCLC. To provide better treatment options, a deeper understanding of the cellular and molecular mechanisms underlying SCLC initiation, progression, metastasis, and acquisition of resistance is required. In this review, we describe the genetic landscape of SCLC, features of the cell of origin, and targeted therapeutic approaches.

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“…Moreover, p27Xic1 is required for Ascl1-induced neurogenesis in Xenopus embryos (Ali et al, 2014). Interestingly, Ascl1 and Prox1 expression are regulated at the transition from NP proliferation to terminal differentiation in the rodent forebrain (Torii et al, 1999).…”

Section: Mnb Promotes Elav Expression In Gcsmentioning

confidence: 99%

Minibrain drives the Dacapo dependent cell cycle exit of neurons in the Drosophila brain by promoting asense and prospero expression

Shaikh¹,

Gutiérrez-Aviño²,

Colonques³

et al. 2016

Development

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A key aim of neurodevelopmental research is to understand how precursor cells decide to stop dividing and commence their terminal differentiation at the correct time and place. Here, we show that minibrain (mnb), the Drosophila ortholog of the Down syndrome candidate gene DYRK1A, is transiently expressed in newborn neuronal precursors known as ganglion cells (GCs). Mnb promotes the cell cycle exit of GCs through a dual mechanism that regulates the expression of the cyclin-dependent kinase inhibitor Dacapo, the homolog of vertebrate p27Kip1 (Cdkn1b). Mnb upregulates the expression of the proneural transcription factor (TF) Asense, which promotes Dacapo expression. Mnb also induces the expression of Prospero, a homeodomain TF that in turn inhibits the expression of Deadpan, a pan-neural TF that represses dacapo. In addition to its effects on Asense and Prospero, Mnb also promotes the expression of the neuronal-specific RNA regulator Elav, strongly suggesting that Mnb facilitates neuronal differentiation. These actions of Mnb ensure the precise timing of neuronal birth, coupling the mechanisms that regulate neurogenesis, cell cycle control and terminal differentiation of neurons.

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The phosphorylation status of Ascl1 is a key determinant of neuronal differentiation and maturation in vivo and in vitro

Cited by 78 publications

References 30 publications

bHLH proteins involved in Drosophila neurogenesis are mutually regulated at the level of stability

bHLH proteins involved in Drosophila neurogenesis are mutually regulated at the level of stability

Origins, genetic landscape, and emerging therapies of small cell lung cancer

Minibrain drives the Dacapo dependent cell cycle exit of neurons in the Drosophila brain by promoting asense and prospero expression

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