Nervous NDRGs: the N-myc downstream-regulated gene family in the central and peripheral nervous system

Abstract

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.

Keywords: Alzheimer’s disease; Cancer; Charcot-Marie-Tooth disease; Dementia; NDRG; Nervous system.

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