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Neurogenetics
2019 Oct 01;204:173-186. doi: 10.1007/s10048-019-00587-0.
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Nervous NDRGs: the N-myc downstream-regulated gene family in the central and peripheral nervous system.
Schonkeren SL
,
Massen M
,
van der Horst R
,
Koch A
,
Vaes N
,
Melotte V
.
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The N-Myc downstream-regulated gene (NDRG) family consists of four members (NDRG1, NDRG2, NDRG3, NDRG4) that are differentially expressed in various organs and function in important processes, like cell proliferation and differentiation. In the last couple of decades, interest in this family has risen due to its connection with several disorders of the nervous system including Charcot-Marie-Tooth disease and dementia, as well as nervous system cancers. By combining a literature review with in silico data analysis of publicly available datasets, such as the Mouse Brain Atlas, BrainSpan, the Genotype-Tissue Expression (GTEx) project, and Gene Expression Omnibus (GEO) datasets, this review summarizes the expression and functions of the NDRG family in the healthy and diseased nervous system. We here show that the NDRGs have a differential, relatively cell type-specific, expression pattern in the nervous system. Even though NDRGs share functionalities, like a role in vesicle trafficking, stress response, and neurite outgrowth, other functionalities seem to be unique to a specific member, e.g., the role of NDRG1 in myelination. Furthermore, mutations, phosphorylation, or changes in expression of NDRGs are related to nervous system diseases, including peripheral neuropathy and different forms of dementia. Moreover, NDRG1, NDRG2, and NDRG4 are all involved in cancers of the nervous system, such as glioma, neuroblastoma, or meningioma. All in all, our review elucidates that although the NDRGs belong to the same gene family and share some functional features, they should be considered unique in their expression patterns and functional importance for nervous system development and neuronal diseases.
Fig. 1. Temporal expression patterns of the NDRG family members during development. a Expression in developing wild-type mouse brain at three time points: embryonal day 14 (E14), postnatal day 0 (P0), and postnatal day 14 (P14). Expression values are Robust Multi-array Averages (RMA), corrected for background, log2 transformed, and quantile-normalized. Data were obtained from GEO (GSE35366) and analyzed using R (version 3.5.3). b Expression of the NDRGs in human brain samples throughout development, ranging from early prenatal stage to adulthood. Expression values are expressed as Reads per Kilobase Million (RPKM) ± SEM. Data were obtained from BrainSpan (http://www.brainspan.org/) and analyzed using the R2 Genomics Analysis and Visualization Platform (https://hgserver1.amc.nl/cgi-bin/r2/main.cgi).
Fig. 2. Spatial expression patterns of the NDRG genes in nervous system tissues and cell types. a RNA sequencing expression of the NDRG family members in the tibial nerve and different brain regions (human). The data used for the analyses were obtained from the GTEx project (v7) on 18/03/2019. TPM = Transcripts Per kilobase Million ± SEM. b Affymetrix GeneChip array expression analysis of the NDRG family members per cell type. Expression values are normalized using MAS5.0, data obtained from GEO (GSE9566). c Single-cell RNA sequencing expression of the NDRG family members in the nervous system. The data used for the analyses were obtained from http://mousebrain.org/genesearch.html on October 5, 2019. Abbreviations in b, c are as follows: Myelin OLs, myelinating oligodendrocytes; OLs, oligodendrocytes; OPCs, oligodendrocyte precursor cells; ENS, enteric nervous system; Exc N, excitatory neurons; MB Inh, midbrain inhibitory neurons; Str, striatum; Hyp, hypothalamus; BG, basal ganglia (thalamus and pallidum); OB, olfactory bulb; CB, cerebellum; SC, spinal cord; PNS, peripheral nervous system; Vasc, vascular cells
Fig. 3. Functional pathways influenced by NDRG1, NDRG2, NDRG3, and NDRG4. a Distinct functional pathways for NDRG1, NDRG2, and NDRG4. b Shared functional pathways induced by ischemia and stress involving more than one NDRG family member. LDL, low-density lipoprotein; Olig2, oligodendrocyte lineage transcription factor 2; PRA1, Prenylated Rab Acceptor 1; BDNF, brain-derived neurotrophic factor; AP-1, activator protein 1; Snap25, synaptosomal-associated protein 25; SGK1, serum/glucocorticoid-regulated kinase 1; OL, oligodendrocyte; GLAST, glutamate transporter glutamate aspartate transporter; GLT-1, glutamate transporter 1
Ai,
NDRG1 overexpression promotes the progression of esophageal squamous cell carcinoma through modulating Wnt signaling pathway.
2016, Pubmed
Ai,
NDRG1 overexpression promotes the progression of esophageal squamous cell carcinoma through modulating Wnt signaling pathway.
2016,
Pubmed
Berger,
Expression analysis of the N-Myc downstream-regulated gene 1 indicates that myelinating Schwann cells are the primary disease target in hereditary motor and sensory neuropathy-Lom.
2004,
Pubmed
Blaes,
NDRG1 prognosticates the natural course of disease in WHO grade II glioma.
2014,
Pubmed
Cahoy,
A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function.
2008,
Pubmed
Chrast,
Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models.
2011,
Pubmed
Deng,
N-Myc downstream-regulated gene 2 (NDRG2) inhibits glioblastoma cell proliferation.
2003,
Pubmed
Ding,
NDRG4 is downregulated in glioblastoma and inhibits cell proliferation.
2012,
Pubmed
Du,
MicroRNA31-NDRG3 regulation axes are essential for hepatocellular carcinoma survival and drug resistance.
2017,
Pubmed
Echaniz-Laguna,
NDRG1-linked Charcot-Marie-Tooth disease (CMT4D) with central nervous system involvement.
2007,
Pubmed
Ellen,
NDRG1, a growth and cancer related gene: regulation of gene expression and function in normal and disease states.
2008,
Pubmed
Flügge,
NDRG2 as a marker protein for brain astrocytes.
2014,
Pubmed
Fontenas,
Neuronal Ndrg4 Is Essential for Nodes of Ranvier Organization in Zebrafish.
2016,
Pubmed
Herskowitz,
Phosphoproteomic analysis reveals site-specific changes in GFAP and NDRG2 phosphorylation in frontotemporal lobar degeneration.
2010,
Pubmed
Hongo,
Ndrg4 enhances NGF-induced ERK activation uncoupled with Elk-1 activation.
2006,
Pubmed
Hu,
Expression analysis of the NDRG2 gene in mouse embryonic and adult tissues.
2006,
Pubmed
Jin,
Spatiotemporal expression of NDRG2 in the human fetal brain.
2019,
Pubmed
Jóźwiak-Bebenista,
[The neuroprotective effect of PACAP, VIP, and derivatives in brain ischemia].
2008,
Pubmed
Kalaydjieva,
N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom.
2000,
Pubmed
King,
Ndrg1 in development and maintenance of the myelin sheath.
2011,
Pubmed
Kolodziej,
NDRG2 and NDRG4 Expression Is Altered in Glioblastoma and Influences Survival in Patients with MGMT-methylated Tumors.
2016,
Pubmed
Kotipatruni,
NDRG4 is a novel oncogenic protein and p53 associated regulator of apoptosis in malignant meningioma cells.
2015,
Pubmed
Kotipatruni,
NDRG4, the N-Myc downstream regulated gene, is important for cell survival, tumor invasion and angiogenesis in meningiomas.
2012,
Pubmed
Kovacevic,
The metastasis suppressor, Ndrg-1: a new ally in the fight against cancer.
2006,
Pubmed
Kumar,
A review on Alzheimer's disease pathophysiology and its management: an update.
2015,
Pubmed
Lachat,
Expression of NDRG1, a differentiation-related gene, in human tissues.
2002,
Pubmed
Le,
Ndrg2 deficiency ameliorates neurodegeneration in experimental autoimmune encephalomyelitis.
2018,
Pubmed
Li,
Downregulation of N-Myc downstream-regulated gene 4 influences patient survival in gliomas.
2013,
Pubmed
Li,
Intelectin 1 suppresses the growth, invasion and metastasis of neuroblastoma cells through up-regulation of N-myc downstream regulated gene 2.
2015,
Pubmed
Li,
Spatial-temporal expression of NDRG2 in rat brain after focal cerebral ischemia and reperfusion.
2011,
Pubmed
Li,
NDRG2 is a novel p53-associated regulator of apoptosis in C6-originated astrocytes exposed to oxygen-glucose deprivation.
2013,
Pubmed
Li,
FOXD3 is a novel tumor suppressor that affects growth, invasion, metastasis and angiogenesis of neuroblastoma.
2013,
Pubmed
Li,
Decreased expression of NDRG2 is related to poor overall survival in patients with glioma.
2011,
Pubmed
Li,
The growth-inhibitory Ndrg1 gene is a Myc negative target in human neuroblastomas and other cell types with overexpressed N- or c-myc.
2003,
Pubmed
Liang,
Gene expression profiles in anatomically and functionally distinct regions of the normal aged human brain.
2007,
Pubmed
Lusis,
Integrative genomic analysis identifies NDRG2 as a candidate tumor suppressor gene frequently inactivated in clinically aggressive meningioma.
2005,
Pubmed
Ma,
Overexpression of N-myc downstream-regulated gene 1 inhibits human glioma proliferation and invasion via phosphoinositide 3-kinase/AKT pathways.
2015,
Pubmed
Ma,
High expression of NDRG3 associates with positive lymph node metastasis and unfavourable overall survival in laryngeal squamous cell carcinoma.
2016,
Pubmed
Maeda,
Genomic organization, expression, and comparative analysis of noncoding region of the rat Ndrg4 gene.
2004,
Pubmed
Matschke,
NDRG2 phosphorylation provides negative feedback for SGK1-dependent regulation of a kainate receptor in astrocytes.
2015,
Pubmed
Matsushita,
Low NDRG1 mRNA expression predicts a poor prognosis in neuroblastoma patients.
2013,
Pubmed
Melotte,
The N-myc downstream regulated gene (NDRG) family: diverse functions, multiple applications.
2010,
Pubmed
Miller,
Transcriptional landscape of the prenatal human brain.
2014,
Pubmed
Mitchelmore,
NDRG2: a novel Alzheimer's disease associated protein.
2004,
Pubmed
Miyata,
Plasma corticosterone activates SGK1 and induces morphological changes in oligodendrocytes in corpus callosum.
2011,
Pubmed
Miyata,
Disturbance of oligodendrocyte function plays a key role in the pathogenesis of schizophrenia and major depressive disorder.
2015,
Pubmed
Nakada,
Molecular characterization of NDRG4/Bdm1 protein isoforms that are differentially regulated during rat brain development.
2002,
Pubmed
Ohki,
Inhibition of neurite outgrowth by reduced level of NDRG4 protein in antisense transfected PC12 cells.
2002,
Pubmed
Okamoto,
Exonic duplication CNV of NDRG1 associated with autosomal-recessive HMSN-Lom/CMT4D.
2014,
Pubmed
Okuda,
Identification of new genes ndr2 and ndr3 which are related to Ndr1/RTP/Drg1 but show distinct tissue specificity and response to N-myc.
1999,
Pubmed
Okuda,
Ndrg1-deficient mice exhibit a progressive demyelinating disorder of peripheral nerves.
2004,
Pubmed
Okuda,
Differential expression patterns of NDRG family proteins in the central nervous system.
2008,
Pubmed
Omuro,
Glioblastoma and other malignant gliomas: a clinical review.
2013,
Pubmed
Ongaratti,
Expression of merlin, NDRG2, ERBB2, and c-MYC in meningiomas: relationship with tumor grade and recurrence.
2016,
Pubmed
Pietiäinen,
NDRG1 functions in LDL receptor trafficking by regulating endosomal recycling and degradation.
2013,
Pubmed
Pramparo,
Global developmental gene expression and pathway analysis of normal brain development and mouse models of human neuronal migration defects.
2011,
Pubmed
Qu,
Characterization and expression of three novel differentiation-related genes belong to the human NDRG gene family.
2002,
Pubmed
Qu,
Ndrg4 is required for normal myocyte proliferation during early cardiac development in zebrafish.
2008,
Pubmed
Ren,
Prognostic impact of NDRG2 and NDRG3 in prostate cancer patients undergoing radical prostatectomy.
2014,
Pubmed
Rong,
The pathological roles of NDRG2 in Alzheimer's disease, a study using animal models and APPwt-overexpressed cells.
2017,
Pubmed
Said,
Oxygen-dependent regulation of NDRG1 in human glioblastoma cells in vitro and in vivo.
2009,
Pubmed
Schilling,
NDRG4 is required for cell cycle progression and survival in glioblastoma cells.
2009,
Pubmed
Schwartzbaum,
Epidemiology and molecular pathology of glioma.
2006,
Pubmed
Shen,
Immunohistochemical detection of Ndrg2 in the mouse nervous system.
2008,
Pubmed
Shen,
Tumor suppressor NDRG2 tips the balance of oncogenic TGF-β via EMT inhibition in colorectal cancer.
2014,
Pubmed
Skiriute,
Tumor grade-related NDRG2 gene expression in primary and recurrent intracranial meningiomas.
2011,
Pubmed
Skiriutė,
Promoter methylation of AREG, HOXA11, hMLH1, NDRG2, NPTX2 and Tes genes in glioblastoma.
2013,
Pubmed
Skiriutė,
Glioma Malignancy-Dependent NDRG2 Gene Methylation and Downregulation Correlates with Poor Patient Outcome.
2014,
Pubmed
Stein,
NDRG1 is necessary for p53-dependent apoptosis.
2004,
Pubmed
Sun,
Decreased expression of NDRG1 in glioma is related to tumor progression and survival of patients.
2009,
Pubmed
Takahashi,
Ndrg2 promotes neurite outgrowth of NGF-differentiated PC12 cells.
2005,
Pubmed
Takeichi,
The effect of Ndrg2 expression on astroglial activation.
2011,
Pubmed
Tazir,
Autosomal recessive Charcot-Marie-Tooth disease: from genes to phenotypes.
2013,
Pubmed
Tepel,
Frequent promoter hypermethylation and transcriptional downregulation of the NDRG2 gene at 14q11.2 in primary glioblastoma.
2008,
Pubmed
Vaes,
NDRG4, an early detection marker for colorectal cancer, is specifically expressed in enteric neurons.
2017,
Pubmed
Vaes,
A combined literature and in silico analysis enlightens the role of the NDRG family in the gut.
2018,
Pubmed
Wakisaka,
Cellular distribution of NDRG1 protein in the rat kidney and brain during normal postnatal development.
2003,
Pubmed
Wang,
Electroacupuncture attenuates reference memory impairment associated with astrocytic NDRG2 suppression in APP/PS1 transgenic mice.
2014,
Pubmed
Weiler,
mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy.
2014,
Pubmed
Wen,
NDRG4 protects against cerebral ischemia injury by inhibiting p53-mediated apoptosis.
2019,
Pubmed
Wen,
NDRG4 prevents cerebral ischemia/reperfusion injury by inhibiting neuronal apoptosis.
2019,
Pubmed
Yamamoto,
NDRG4 protein-deficient mice exhibit spatial learning deficits and vulnerabilities to cerebral ischemia.
2011,
Pubmed
Yamauchi,
Molecular cloning and characterization of a novel developmentally regulated gene, Bdm1, showing predominant expression in postnatal rat brain.
1999,
Pubmed
Yang,
NDRG3 and NDRG4, two novel tumor-related genes.
2013,
Pubmed
Yao,
Let-7f Regulates the Hypoxic Response in Cerebral Ischemia by Targeting NDRG3.
2017,
Pubmed
Yao,
NDRG2: a Myc-repressed gene involved in cancer and cell stress.
2008,
Pubmed
You,
Death-associated protein kinase 1 phosphorylates NDRG2 and induces neuronal cell death.
2017,
Pubmed
Zeisel,
Molecular Architecture of the Mouse Nervous System.
2018,
Pubmed
Zhang,
Overexpression of NDRG2 can inhibit neuroblastoma cell proliferation through negative regulation by CYR61.
2014,
Pubmed
Zhong,
Developmental expression of the N-myc downstream regulated gene (Ndrg) family during Xenopus tropicalis embryogenesis.
2015,
Pubmed
,
Xenbase
Zhou,
Tumor suppressor candidate gene, NDRG2 is frequently inactivated in human glioblastoma multiforme.
2014,
Pubmed
Zhou,
Characterization of the human NDRG gene family: a newly identified member, NDRG4, is specifically expressed in brain and heart.
2001,
Pubmed
