Id proteins synchronize stemness and anchorage to the niche of neural stem cells

Niola, Francesco; Zhao, Xudong; Singh, Devendra Raj; Castano, Angelica; Sullivan, Ryan J.; Lauria, Mario; Nam, Hyung-song; Zhuang, Yuan; Benezra, Robert; Bernardo, Diego di; Iavarone, Antonio; Lasorella, Anna

doi:10.1038/ncb2490

Cited by 122 publications

(123 citation statements)

References 46 publications

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“…Loss of Id in iGICs induced the bHLH-ID targets Rap1gap and Cdkn1c (13,35) and led to morphological and molecular changes indicative of multilineage neural differentiation (Supplemental Figure 7, A-C). These effects occurred in the absence of signs of apoptosis (Supplemental Figure 7D).…”

Section: Figurementioning

confidence: 99%

“…Id-cTKO) mice (13). HrasV12-Cre-ER-shp53 lentiviral particles were injected in the hippocampi of 4-week-old Id-cTKO mice, and tumor initiation/progression was examined.…”

Section: Suppression Of Id Function Impacts Tumor Maintenance Of Hggmentioning

confidence: 99%

“…However, they can exert different roles depending on the cellular context and the particular biological system (10). During normal development of the brain, ID proteins prevent premature cell fate determination and differentiation (11)(12)(13). Recently, we discovered that ID proteins preserve anchorage of NSCs to the extracellular niche microenvironment by repressing basic helix loop helix-mediated (bHLH-mediated) transcriptional activation of the gene coding for the RAP1-GTPase inhibitor Rap1GAP, thus precluding premature detachment of NSCs from the ventricular surface and initiation of differentiation (13).…”

Section: Introductionmentioning

confidence: 99%

“…During normal development of the brain, ID proteins prevent premature cell fate determination and differentiation (11)(12)(13). Recently, we discovered that ID proteins preserve anchorage of NSCs to the extracellular niche microenvironment by repressing basic helix loop helix-mediated (bHLH-mediated) transcriptional activation of the gene coding for the RAP1-GTPase inhibitor Rap1GAP, thus precluding premature detachment of NSCs from the ventricular surface and initiation of differentiation (13). Accumulation of ID proteins is detected in a variety of tumor types, including HGG, in which the highest levels of ID proteins have been associated with the most aggressive form of the disease, the glioblastoma multiforme (GBM) (14).…”

Section: Introductionmentioning

confidence: 99%

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Mesenchymal high-grade glioma is maintained by the ID-RAP1 axis

Niola¹,

Zhao²,

Singh³

et al. 2012

J. Clin. Invest.

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High-grade gliomas (HGGs) are incurable brain tumors that are characterized by the presence of glioma-initiating cells (GICs). GICs are essential to tumor aggressiveness and retain the capacity for self-renewal and multilineage differentiation as long as they reside in the perivascular niche. ID proteins are master regulators of stemness and anchorage to the extracellular niche microenvironment, suggesting that they may play a role in maintaining GICs. Here, we modeled the probable therapeutic impact of ID inactivation in HGG by selective ablation of Id in tumor cells and after tumor initiation in a new mouse model of human mesenchymal HGG. Deletion of 3 Id genes induced rapid release of GICs from the perivascular niche, followed by tumor regression. GIC displacement was mediated by derepression of Rap1gap and subsequent inhibition of RAP1, a master regulator of cell adhesion. We identified a signature module of 5 genes in the ID pathway, including RAP1GAP, which segregated 2 subgroups of glioma patients with markedly different clinical outcomes. The model-informed survival analysis together with genetic and functional studies establish that ID activity is required for the maintenance of mesenchymal HGG and suggest that pharmacological inactivation of ID proteins could serve as a therapeutic strategy.

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Section: Figurementioning

confidence: 99%

“…Id-cTKO) mice (13). HrasV12-Cre-ER-shp53 lentiviral particles were injected in the hippocampi of 4-week-old Id-cTKO mice, and tumor initiation/progression was examined.…”

Section: Suppression Of Id Function Impacts Tumor Maintenance Of Hggmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Mesenchymal high-grade glioma is maintained by the ID-RAP1 axis

Niola¹,

Zhao²,

Singh³

et al. 2012

J. Clin. Invest.

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“…A previous study (Fraidenraich et al 2004) found that deleting three out of the four Id genes (Id1,2,3 triple gene knockout) caused complex cardiac defects but did not ablate the heart in these embryos, thereby indicating that earlier cardiac specification could still occur. Given the functional similarity of Id family members (Lyden et al 1999;Fraidenraich et al 2004;Kee and Bronner-Fraser 2005;Niola et al 2012Niola et al , 2013, we reasoned that either redundant or compensatory activity of Id4 might allow heart formation to occur in triple-knockout embryos. To test this hypothesis, we genetically ablated all four Id gene members using a CRISPR/Cas9 genome-editing strategy in mouse embryos.…”

Section: Id Proteins Promote Cardiogenic Mesoderm Formation In Vivomentioning

confidence: 99%

Id genes are essential for early heart formation

Cunningham

McKeithan

et al. 2017

Genes Dev.

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Deciphering the fundamental mechanisms controlling cardiac specification is critical for our understanding of how heart formation is initiated during embryonic development and for applying stem cell biology to regenerative medicine and disease modeling. Using systematic and unbiased functional screening approaches, we discovered that the Id family of helix-loop-helix proteins is both necessary and sufficient to direct cardiac mesoderm formation in frog embryos and human embryonic stem cells. Mechanistically, Id proteins specify cardiac cell fate by repressing two inhibitors of cardiogenic mesoderm formation-Tcf3 and Foxa2-and activating inducers Evx1, Grrp1, and Mesp1. Most importantly, CRISPR/Cas9-mediated ablation of the entire Id (Id1-4) family in mouse embryos leads to failure of anterior cardiac progenitor specification and the development of heartless embryos. Thus, Id proteins play a central and evolutionarily conserved role during heart formation and provide a novel means to efficiently produce cardiovascular progenitors for regenerative medicine and drug discovery applications.[Keywords: cardiac progenitors; cardiac mesoderm specification; heartless; Id proteins; CRISPR/Cas9-mediated quadruple knockout; platform for cardiac disease modeling and drug discovery] Supplemental material is available for this article.

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Id1 and Id3 Are Regulated Through Matrix‐Assisted Autocrine BMP Signaling and Represent Therapeutic Targets in Melanoma

Sedlmeier

Al-Rawi

Buchert

et al. 2020

Advanced Therapeutics

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The tumorigenicity of cancer cells is highly influenced by the extracellular matrix (ECM) through mechanisms that are poorly understood. Here it is reported that a variety of 3D ECM microenvironments strongly induce expression of Id1 and Id3 in melanoma cells. Genetic ablation of Id1/Id3 impairs melanoma cell outgrowth in 3D Matrigel culture and inhibits melanoma initiation in vivo. Mechanistically, 3D ECM microenvironments hinder diffusion of endogenously produced bone morphogenetic proteins, thereby fostering autocrine signaling and Id1/Id3 expression. A compound screen identifies new coumarin derivatives that potently inhibit both Id1/Id3 expression and melanoma initiation in vivo. Together, the findings reveal a novel mechanism through which the ECM increases tumorigenicity, identify Id1/Id3 as melanoma-relevant therapeutic targets, and characterize inhibitors of Id1/Id3 expression with therapeutic potential.

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Id proteins synchronize stemness and anchorage to the niche of neural stem cells

Cited by 122 publications

References 46 publications

Mesenchymal high-grade glioma is maintained by the ID-RAP1 axis

Mesenchymal high-grade glioma is maintained by the ID-RAP1 axis

Id genes are essential for early heart formation

Id1 and Id3 Are Regulated Through Matrix‐Assisted Autocrine BMP Signaling and Represent Therapeutic Targets in Melanoma

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