Table 1.
Selected references of Id proteins with various biological and pathophysiological functions in the nervous system.
| Inhibitor of DNA-Binding/Differentiation (Id) Proteins | Relevant Biological and Pathophysiological Roles in the Nervous System | Reference and Potential Mechanisms Involving Id Proteins |
|---|---|---|
| Id1, Id2, and Id3 | Self-renewal and proliferation of cortical neural stem cells | [41]: decrease NeuroD/E47 complexes and E-box-mediated gene expression |
| Id1 | cDNA array analysis of pineal gene expression for circadian rhythm | [59]: Id1, but not Id2 or Id3, mRNA and protein exhibit changes of several folds during day/night rhythms |
| Id1 | Neural stem cell proliferation | [43]: p53 and bone morphogenetic proteins (BMP)-Smad1 pathway |
| Id1 | Involved in neurogenesis and cognitive function | [44]: microRNA-17-92 cluster regulates enigma homolog 1/Id1 signaling |
| Id1 | Involved in intracellular Shh and Wnt signaling in glioblastoma stem cells | [47]: Cullin-3 regulates Id1 expression |
| Id1 | FGF-2 can induce Id1 expression in the human neuroblastoma cell line | [48]: inhibition of Id1 expression results in the accumulation of FGF-2-treated cells at the G2/M stage and postpones cell death |
| Id1 | TSP-1 expression in AVM-CECs | [50]: Id1 negatively regulates TSP-1 expression |
| Id1 | In vivo and in vitro Alzheimer’s disease models | [32,33,34]: Id1, HIF-1, CDK5, and Shh may contribute to Aβ-induced cell cycle reentry in postmitotic neurons; Id1 and CDK5/p25 mutually antagonize the expression/activity of each other (please see Figure 2 for illustration). |
| Id2 | Maintaining normal NPC proliferation | [42]: Id2 functions as a pro-proliferative gene regulated by p53 |
| Id2 | Modulation of hypoxia- and ischemia-induced neuronal apoptosis | [53,54]: hypoxia/ischemia upregulates Id2 expression; Id2 knockdown induces G0/G1 cell cycle arrest |
| Id2 | Impaired proliferation and differentiation of oligodendrocyte precursor cells; limited functional recovery after ischemic stroke | [55]: Id2 is a key factor controlling the differentiation of oligodendrocyte precursor cells |
| Id1, Id2, and Id3 | Increased in astrocytes in response to CNS injury | [56]: Id3 was revealed to play a more evident role in regulating astrocyte proliferation in response to injury |
| Id1, Id2, and Id3 | Rats subjected to electrically induced status epilepticus | [57]: expression levels of Id proteins in the hippocampus are increased in the reactive astrocytes |
| Id1, Id2, and Id3 | Modulating cellular responsiveness to TNF-α and CNS inflammation | [58]: putative role for the Id family, expressed in astrocyte and microglia—mainly Id2 and Id3 and less with Id1 |
| Id4 | PDGF and NOS2 expression levels in glioblastoma cells | [60,61]: Id4 increases PDGF and NOS2 expression levels; this circuit of PDGF-NO-Id4 enhances the self-renewal of glioblastoma cells and PDGF-induced oligodendroglioma |
| Id4 | Genesis of glioma-initiating cells | [62]: via cyclin E and the activation of Notch signaling |
| Id4 | Was differentially expressed in various grades of astrocytoma | [63]: possible transformation of low-to-high-grade astrocytoma (i.e., glioblastoma) |
| Id4 | The ability of growth of glioblastoma | [64]: Id4 was also found to possess proangiogenic functions |
Abbreviations: AVM-CECs: arteriovenous malformations-cerebral endothelial cells, BMP: bone morphogenetic proteins, CDK5: cyclin-dependent kinases-5, CNS: central nervous system, FGF-2: fibroblast growth factor-2, HIF-1: hypoxia-inducible factor-1, PDGF: platelet-derived growth factor, NOS2: nitric oxide synthase 2, NPC: neural progenitor cells, Shh: sonic hedgehog, TNF-α: tumor necrosis factor-alpha, Aβ: amyloid-beta peptides, and TSP-1: thrombospondin-1.