BMP Signaling Induces Astrocytic Differentiation of Clinically Derived Oligodendroglioma Propagating Cells

Srikanth, Maya; Kim, Juno; Das, Sunit; Kessler, John A.

doi:10.1158/1541-7786.mcr-13-0349

Cited by 22 publications

(20 citation statements)

References 42 publications

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“…ID4 is also the downstream target of BMP4 in neural progenitor cells and apparently mediates the inhibitory effects on oligodendroglial differentiation [87, 88] whereas ID4 dependent osteoblast differentiation is independent of BMP4 [24], suggesting cell type specific regulation (Table II). …”

Section: Regulation Of Id4 Gene Expressionmentioning

confidence: 99%

“…Protein interaction studies have demonstrated that ID4 sequesters OLIG1 and OLIG2, members of class B bHLH proteins which plays key roles in early oligodendrocyte specification and regulates oligodendrocyte differentiation [87, 88]. Interestingly OLIG1 and OLIG2 only interact with ID4 and to a lesser extent with ID2 but not with ID1 or ID3.…”

Section: Mechanism Of Action Of Id4mentioning

confidence: 99%

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Inhibitor of differentiation 4 (ID4): From development to cancer

Patel

Morton

Carey

et al. 2015

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Highly conserved Inhibitor of DNA Binding (ID1-4) genes encode multi-functional proteins whose transcriptional activity is based on dominant negative inhibition of basic helix-loop-helix (bHLH) transcription factors. Initial animal models indicated a degree of compensatory overlap between ID genes such that deletion of multiple ID genes was required to generate easily recognizable phenotypes. More recently, new model systems have revealed alterations in mice harboring deletions in single ID genes suggesting complex gene and tissue specific functions for members of the ID gene family. Because ID genes are highly expressed during development and their function is associated with a primitive, proliferative cellular phenotype there has been significant interest in understanding their potential roles in neoplasia. Indeed, numerous studies indicate an oncogenic function for ID1, 2 and 3. In contrast, the inhibitor of differentiation 4 (ID4) presents a paradigm shift in context of well-established role of ID1, 2 and 3 in development and cancer. Apart from some degree of functional redundancy such as HLH dependent interactions with bHLH protein E2A, many of the functions of ID4 are distinct from ID1, 2 and 3: ID4 proteins a) regulate distinct developmental processes and tissue expression in the adult, b) promotes stem cell survival, differentiation and/or timing of differentiation, c) epigenetic inactivation/loss of expression in several advanced stage cancers and d) increased expression in some cancers such as those arising in the breast and ovary. Thus, in spite of sharing the conserved HLH domain, ID4 defies the established model of ID protein function and expression. The underlying molecular mechanism responsible for the unique role of ID4 as compared to other ID proteins still remains largely un-explored. This review will focus on the current understanding of ID4 in context of development and cancer.

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Section: Regulation Of Id4 Gene Expressionmentioning

confidence: 99%

Section: Mechanism Of Action Of Id4mentioning

confidence: 99%

Inhibitor of differentiation 4 (ID4): From development to cancer

Patel

Morton

Carey

et al. 2015

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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“…One potential approach to blocking tumor growth and invasion is to induce them to become terminally differentiated cells. Indeed, previous studies demonstrate that glioma cells can be induced to undergo glial differentiation by the microRNA (miR)-146a, 4 miR-34a, 5 activation of the bone morphogenic protein signaling, 6 , 7 all-trans retinoic acid, 8 or small molecules targeting mutant isocitrate dehydrogenase 1 or inhibitors of apoptosis proteins. 9 , 10 The miR-124 and miR-137 are also able to induce glioma cells to adopt a neuron-like fate.…”

mentioning

confidence: 99%

Reprogramming the fate of human glioma cells to impede brain tumor development

Zang

Liu

et al. 2014

Cell Death Dis

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Malignant gliomas, the most common solid tumors in the central nervous system, are essentially incurable due to their rapid growth and very invasive nature. One potential approach to eradicating glioma cells is to force these cells to undergo terminal differentiation and, in the process, to irreversible postmitotic arrest. Here, we show that neurogenin 2 (NGN2, also known as NEUROG2) synergizes with sex-determining region Y-box 11 (SOX11) to very efficiently convert human glioma cells to terminally differentiated neuron-like cells in both cell culture and adult mouse brains. These cells exhibit neuronal morphology, marker expression, and electrophysiological properties. The conversion process is accompanied by cell cycle exit, which dramatically inhibits glioma cell proliferation and tumor development after orthotopic transplantation. Most importantly, intracranial injection of NGN2- and SOX11-expressing virus into the tumor mass also curtails glioma growth and significantly improves survival of tumor-bearing mice. Taken together, this study shows a simple and highly efficient strategy for reprogramming malignant glioma cells into postmitotic cells, which might be a promising therapeutic approach for brain tumors.

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“…In general, BMP signaling is thought to inhibit oligodendrogliogenesis during development, and this is supported by studies in which cultured NPCs are stimulated to differentiate into astrocytes after treatment with BMPs [7, 31, 32]. Furthermore, expression of noggin in areas of BMP expression overcomes the inhibitory nature of BMPs and allows OL formation [33].…”

Section: Discussionmentioning

confidence: 99%

Targeted Knockdown of Bone Morphogenetic Protein Signaling within Neural Progenitors Protects the Brain and Improves Motor Function following Postnatal Hypoxia-Ischemia

Dettman¹,

Birch

Fernando

et al. 2018

Dev Neurosci

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Hypoxic-ischemic injury (HI) to the neonatal human brain results in myelin loss that, in some children, can manifest as cerebral palsy. Previously, we had found that neuronal overexpression of the bone morphogenic protein (BMP) inhibitor noggin during development increased oligodendroglia and improved motor function in an experimental model of HI utilizing unilateral common carotid artery ligation followed by hypoxia. As BMPs are known to negatively regulate oligodendroglial fate specification of neural stem cells and alter differentiation of committed oligodendroglia, BMP signaling is likely an important mechanism leading to myelin loss. Here, we showed that BMP signaling is upregulated within oligodendroglia of the neonatal brain. We tested the hypothesis that inhibition of BMP signaling specifically within neural progenitor cells (NPCs) is sufficient to protect oligodendroglia. We conditionally deleted the BMP receptor 2 subtype (BMPR2) in NG2-expressing cells after HI. We found that BMPR2 deletion globally protects the brain as assessed by MRI and protects motor function as assessed by digital gait analysis, and that conditional deletion of BMPR2 maintains oligodendrocyte marker expression by immunofluorescence and Western blot and prevents loss of oligodendroglia. Finally, BMPR2 deletion after HI results in an increase in noncompacted myelin. Thus, our data indicate that inhibition of BMP signaling specifically in NPCs may be a tractable strategy to protect the newborn brain from HI.

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BMP Signaling Induces Astrocytic Differentiation of Clinically Derived Oligodendroglioma Propagating Cells

Cited by 22 publications

References 42 publications

Inhibitor of differentiation 4 (ID4): From development to cancer

Inhibitor of differentiation 4 (ID4): From development to cancer

Reprogramming the fate of human glioma cells to impede brain tumor development

Targeted Knockdown of Bone Morphogenetic Protein Signaling within Neural Progenitors Protects the Brain and Improves Motor Function following Postnatal Hypoxia-Ischemia

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