Noise-Induced Dysregulation of Quaking RNA Binding Proteins Contributes to Auditory Nerve Demyelination and Hearing Loss.

Noise exposure causes auditory nerve (AN) degeneration and hearing deficiency, though the proximal biological consequences are not entirely understood. Most AN fibers and spiral ganglion neurons are ensheathed by myelinating glia that provide insulation and ensure rapid transmission of nerve impulses from the cochlea to the brain. Here we show that noise exposure administered to mice of either sex rapidly affects myelinating glial cells, causing molecular and cellular consequences that precede nerve degeneration. This response is characterized by demyelination, inflammation, and widespread expression changes in myelin-related genes, including the RNA splicing regulator Quaking (QKI) and numerous QKI target genes. Analysis of mice deficient in QKI revealed that QKI production in cochlear glial cells is essential for proper myelination of spiral ganglion neurons and AN fibers, and for normal hearing. Our findings implicate QKI dysregulation as a critical early component in the noise response, influencing cochlear glia function that leads to AN demyelination and, ultimately, to hearing deficiency.SIGNIFICANCE STATEMENT Auditory glia cells ensheath a majority of spiral ganglion neurons with myelin, protect auditory neurons, and allow for fast conduction of electrical impulses along the auditory nerve. Here we show that noise exposure causes glial dysfunction leading to myelin abnormality and altered expression of numerous genes in the auditory nerve, including QKI, a gene implicated in regulating myelination. Study of a conditional mouse model that specifically depleted QKI in glia showed that QKI deficiency alone was sufficient to elicit myelin-related abnormality and auditory functional declines. These results establish QKI as a key molecular target in the noise response and a causative agent in hearing loss.

Oligodendroglial defects during quakingviable cerebellar development.

The selective RNA-binding protein Quaking I (QKI) has previously been implicated in RNA localization and stabilization, alternative splicing, cell proliferation, and differentiation. The spontaneously-occurring quakingviable (qkv) mutant mouse exhibits a sharply attenuated level of QKI in myelin-producing cells, including oligodendrocytes (OL) because of the loss of an OL-specific promoter. The disruption of QKI in OLs results in severe hypomyelination of the central nervous system, but the underlying cellular mechanisms remain to be fully elucidated. In this study, we used the qkv mutant mouse as a model to study myelination defects in the cerebellum. We found that oligodendroglial development and myelination are adversely affected in the cerebellum of qkv mice. Specifically, we identified an increase in the total number of oligodendroglial precursor cells in qkv cerebella, a substantial portion of which migrated into the grey matter. Furthermore, these mislocalized oligodendroglial precursor cells retained their migratory morphology late into development. Interestingly, a number of these presumptive oligodendrocyte precursors were found at the Purkinje cell layer in qkv cerebella, resembling Bergman glia. These findings indicate that QKI is involved in multiple aspects of oligodendroglial development. QKI disruption can impact the cell fate of oligodendrocyte precursor cells, their migration and differentiation, and ultimately myelination in the cerebellum. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 972-982, 2016.

A cytoplasmic quaking I isoform regulates the hnRNP F/H-dependent alternative splicing pathway in myelinating glia.

The selective RNA-binding protein quaking I (QKI) plays important roles in controlling alternative splicing (AS). Three QKI isoforms are broadly expressed, which display distinct nuclear-cytoplasmic distribution. However, molecular mechanisms by which QKI isoforms control AS, especially in distinct cell types, still remain elusive. The quakingviable (qk(v)) mutant mice carry deficiencies of all QKI isoforms in oligodendrocytes (OLs) and Schwann cells (SWCs), the myelinating glia of central and peripheral nervous system (CNS and PNS), respectively, resulting in severe dysregulation of AS. We found that the cytoplasmic isoform QKI-6 regulates AS of polyguanine (G-run)-containing transcripts in OLs and rescues aberrant AS in the qk(v) mutant by repressing expression of two canonical splicing factors, heterologous nuclear ribonucleoproteins (hnRNPs) F and H. Moreover, we identified a broad spectrum of in vivo functional hnRNP F/H targets in OLs that contain conserved exons flanked by G-runs, many of which are dysregulated in the qk(v) mutant. Interestingly, AS targets of the QKI-6-hnRNP F/H pathway in OLs are differentially affected in SWCs, suggesting that additional cell-type-specific factors modulate AS during CNS and PNS myelination. Together, our studies provide the first evidence that cytoplasmic QKI-6 acts upstream of hnRNP F/H, which forms a novel pathway to control AS in myelinating glia.

Quaking, an RNA-binding protein, is a critical regulator of vascular smooth muscle cell phenotype.

RATIONALE: RNA-binding proteins are critical post-transcriptional regulators of RNA and can influence pre-mRNA splicing, RNA localization, and stability. The RNA-binding protein Quaking (QKI) is essential for embryonic blood vessel development. However, the role of QKI in the adult vasculature, and in particular in vascular smooth muscle cells (VSMCs), is currently unknown. OBJECTIVE: We sought to determine the role of QKI in regulating adult VSMC function and plasticity. METHODS AND RESULTS: We identified that QKI is highly expressed by neointimal VSMCs of human coronary restenotic lesions, but not in healthy vessels. In a mouse model of vascular injury, we observed reduced neointima hyperplasia in Quaking viable mice, which have decreased QKI expression. Concordantly, abrogation of QKI attenuated fibroproliferative properties of VSMCs, while potently inducing contractile apparatus protein expression, rendering noncontractile VSMCs with the capacity to contract. We identified that QKI localizes to the spliceosome, where it interacts with the myocardin pre-mRNA and regulates the splicing of alternative exon 2a. This post-transcriptional event impacts the Myocd_v3/Myocd_v1 mRNA balance and can be modulated by mutating the quaking response element in exon 2a of myocardin. Furthermore, we identified that arterial damage triggers myocardin alternative splicing and is tightly coupled with changes in the expression levels of distinct QKI isoforms. CONCLUSIONS: We propose that QKI is a central regulator of VSMC phenotypic plasticity and that intervention in QKI activity can ameliorate pathogenic, fibroproliferative responses to vascular injury.

Structural bases for central nervous system malfunction in the quaking mouse: dysmyelination in a potential model of schizophrenia.

The dysmyelinating mouse mutant quaking (qk) is thought to be a model of schizophrenia based on diminution of CNS myelin (Andreone et al., 2007) and downregulation of the Qk gene (Haroutunian et al., 2006) in the brains of schizophrenic patients. The purpose of this study was to identify specific structural defects in the qk mouse CNS that could compromise physiologic function and that in humans might account for some of the cognitive defects characteristic of schizophrenia. Ultrastructural analysis of qk mouse CNS myelinated fibers shows abnormalities in nodal, internodal, and paranodal regions, including marked variation in myelin thickness among neighboring fibers, spotty disruption of paranodal junctions, abnormal distribution of nodal and paranodal ion channel complexes, generalized thinning and incompactness of myelin, and on many axonal profiles complete absence of myelin. These structural defects are likely to cause abnormalities in conduction velocity, synchrony of activation, temporal ordering of signals, and other physiological parameters. We conclude that the structural abnormalities described are likely to be responsible for significant functional impairment both in the qk mouse CNS and in the human CNS with comparable myelin pathology.

The QKI-PLP pathway controls SIRT2 abundance in CNS myelin.

Sirtuin 2 (SIRT2), a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase expressed by oligodendrocytes (OLs), the myelin-producing cells of the central nervous system (CNS), is markedly up-regulated during active myelination (Li et al. (2007) J Neurosci 27:2606-2616; Southwood et al. (2007) Neurochem Res 32:187-195; Werner et al. (2007) J Neurosci 27:7717-7730). SIRT2 is a component of the myelin proteome and is severely reduced in the Plp1 knockout mouse brain, in which both proteolipid protein (PLP) and DM20 are absent (Werner et al. (2007) J Neurosci 27:7717-7730). The mechanisms that regulate SIRT2 expression in OLs and myelin remain to be investigated. We report for the first time that the expression of SIRT2 is regulated by the QKI-dependent pathway and this effect is mediated through selective regulation of PLP. In the homozygous quakingviable (qk(v) /qk(v) ) mutant mouse that harbors QKI deficiency in OLs (Bockbrader and Feng (2008) Future Neurol 3:655-668; Ebersole et al. (1996) Nat Genet 12:260-265; Hardy et al. (1996) J Neurosci 16:7941-7949), PLP, but not DM20 mRNA, was selectively down-regulated and SIRT2 protein was severely reduced whereas SIRT2 mRNA expression was unaffected. Expression of the cytoplasmic isoform QKI6 in OLs (Zhao et al. (2006) J Neurosci 26:11278-11286) rescued SIRT2 expression in the qk(v) /qk(v) mutant concomitantly with restoration of PLP expression. Moreover, SIRT2 protein is diminished in myelin tracts and compact myelin of the PLP-ISEdel mutant brain, in which PLP protein but not DM20 is selectively reduced (Wang et al. (2008) Exp Neurol 214:322-330). In contrast, SIRT2 expression and its cellular function in regulating process complexity are not affected by the absence of PLP in PLP-ISEdel non-myelinating OLs. Collectively, our results indicate that the abundance of SIRT2 in myelin is dependent on PLP, but not DM20.

Patched1 haploinsufficiency impairs ependymal cilia function of the quaking viable mice, leading to fatal hydrocephalus.

The quaking viable (qk(v)) mice harbor an autosomal recessive mutation that deletes the parkin co-regulated gene (pacrg) and parkin (park2) genes, and alters the expression of the quaking (qkI) gene. qk(v) mice have been well-studied for their dysmyelination phenotype caused by the altered expression of the qkI gene. The qk(v) mice exhibit sterility in males and develop acquired mild hydrocephalus due to the lack of PACRG expression. To identify genetic interactors of the pacrg-parkin-qkI locus, we crossbred the qk(v) mice with various mouse strains including the patched1 (ptch1)-deficient mice. The ptch1 heterozygous mice exhibit increased Sonic Hedgehog (Shh) signaling and are prone to several malignancies including tumorigenesis. In the present study, we show that the qk(v/v); ptch1⁺/⁻ mice are distinguished by a dome-shaped skull at 4 to 6weeks of age and exhibit dilation of the lateral and third ventricles leading to fatal acquired hydrocephalus by ~5months of age, unlike their littermate controls that did not develop the condition. The qk(v/v); ptch1⁺/⁻ mice contained normal ciliated ependymal cells lining the ventricles of the brain, but these cells were functionally compromised with a severe cilial mediated flow defect. Our findings suggest that the ptch1 and the pacrg-parkin-qkI loci genetically interact to regulate cilia function of the ependymal cells.

Loss of p53 in quaking viable mice leads to Purkinje cell defects and reduced survival.

The qk(v) mutation is a one megabase deletion resulting in abnormal expression of the qkI gene. qk(v) mice exhibit hypomyelination of the central nervous system and display rapid tremors and seizures as adults. The qkI locus on 6q26-27 has also been implicated as a candidate tumor suppressor gene as the qkI locus maps to a region of genetic instability in Glioblastoma Multiforme (GBM), an aggressive brain tumor of astrocytic lineage. As GBM frequently harbors mutations affecting p53, we crossbred qk(v) and p53 mutant mice to examine whether qk(v) mice on a p53(-/-) background have an increased incidence of GBM. qk(v) (/v); p53(-/-) mice had a reduced survival rate compared to p53(-/-) littermates, and the cause of death of the majority of the mice remains unknown. In addition, immunohistochemistry revealed Purkinje cell degeneration in the cerebellum. These results suggest that p53 and qkI are genetically linked for neuronal maintenance and survival.

Deletion of the Parkin co-regulated gene causes defects in ependymal ciliary motility and hydrocephalus in the quakingviable mutant mouse.

The quakingviable mouse (qkv) is a spontaneous recessive mouse mutant with a deletion of approximately 1.1 Mb in the proximal region of chromosome 17. The deletion affects the expression of three genes; quaking (Qk), Parkin-coregulated gene (Pacrg) and parkin (Park2). The resulting phenotype, which includes dysmyelination of the central nervous system and male sterility, is due to reduced expression of Qk and a complete lack of Pacrg expression, respectively. Pacrg is required for correct development of the spermatozoan flagella, a specialized type of motile cilia. In vertebrates, motile cilia are required for multiple functions related to cellular movement or movement of media over a stationary cell surface. To investigate the potential role of PACRG in motile cilia we analysed qkv mutant mice for evidence of cilial dysfunction. Histological and magnetic resonance imaging analyses demonstrated that qkv mutant mice were affected by acquired, communicating hydrocephalus (HC). Structural analysis of ependymal cilia demonstrated that the 9 + 2 arrangement of axonemal microtubules was intact and that both the density of ciliated cells and cilia length was similar to wild-type littermates. Cilia function studies showed a reduction in ependymal cilial beat frequency and cilial mediated flow in qkv mutant mice compared with wild-type littermate controls. Moreover, transgenic expression of Pacrg was necessary and sufficient to correct this deficit and rescue the HC phenotype in the qkv mutant. This study provides novel in vivo evidence that Pacrg is required for motile cilia function and may be involved in the pathogenesis of human ciliopathies, such as HC, asthenospermia and primary ciliary dyskinesia.

Three-dimensional statistical modeling of neuronal populations: illustration with spatial localization of supernumerary neurons in the locus coeruleus of quaking mutant mice.

An algorithm for the three-dimensional statistical representation of neuronal populations was designed and implemented. Using this algorithm a series of 3D models, calculated from repeated histological experiments, can be combined to provide a synthetic vision of a population of neurons taking into account biological and experimental variability. Based on the point process theory, our algorithm allows computation of neuronal density maps from which isodensity surfaces can be readily extracted and visualized as surface models revealing the statistical organization of the neuronal population under study. This algorithm was applied to the spatial distribution of locus coeruleus (LC) neurons of 30- and 90-day-old control and quaking mice. By combining 12 3D models of the LC, a region of the nucleus in which a subpopulation of neurons loses its noradrenergic phenotype between 30 and 90 days postnatally was demonstrated in control mice but not in quaking mice, leading to the hyperplasia previously reported in adult mutants. Altogether, this algorithm allows computation of 3D statistical and graphical models of neuronal populations, providing a contribution to quantitative 3D neuroanatomical modeling.

Post-transcriptional regulation of myelin formation.

Myelin is a specialized structure of the nervous system that both enhances electrical conductance and protects neurons from degeneration. In the central nervous system, extensively polarized oligodendrocytes form myelin by wrapping cellular processes in a spiral pattern around neuronal axons. Myelin formation requires the oligodendrocyte to regulate gene expression in response to changes in its extracellular environment. Because these changes occur at a distance from the cell body, post-transcriptional control of gene expression allows the cell to fine-tune its response. Here, we review the RNA-binding proteins that control myelin formation in the brain, highlighting the molecular mechanisms by which they control gene expression and drawing parallels from studies in other cell types.

New implications for the QUAKING RNA binding protein in human disease.

The use of spontaneously occurring mouse models has proved to be a valuable tool throughout the years to delineate the signals required for nervous system development. This is especially true in the field of myelin biology, with a large number of different models available. The quaking viable mouse models dysmyelination in the nervous system and links the QUAKING RNA binding proteins to myelination and cell fate decisions. In this Mini-Review, we highlight the biological functions attributed to this KH-type RNA binding protein and the recent achievements linking it to human disorders.

Rescuing qkV dysmyelination by a single isoform of the selective RNA-binding protein QKI.

Alternative splicing of the qkI transcript generates multiple isoforms of the selective RNA-binding protein QKI, which play key roles in controlling the homeostasis of their mRNA targets. QKI deficiency in oligodendrocytes of homozygous quakingviable (qkV/qkV) mutant mice results in severe hypomyelination, indicating the essential function of QKI in myelinogenesis. However, the molecular mechanisms by which QKI controls myelination remain elusive. We report here that QKI-6 is the most abundant isoform in brain and is preferentially reduced in the qkV/qkV mutant during normal myelinogenesis. To test whether QKI-6 is the predominant isoform responsible for advancing CNS myelination, we developed transgenic mice that express Flag-QKI-6 specifically in the oligodendroglia lineage, driven by the proteolipid protein (PLP) promoter. When introduced into the qkV/qkV mutant, the QKI-6 transgene rescues the severe tremor and hypomyelination phenotype. Electron microscopic studies further revealed that the Flag-QKI-6 transgene is sufficient for restoring compact myelin formation with normal lamellar periodicity and thickness. Interestingly, Flag-QKI-6 preferentially associates with the mRNA encoding the myelin basic protein (MBP) and rescues MBP expression from the beginning of myelinogenesis. In contrast, Flag-QKI-6 binds the PLP mRNA with lower efficiency and has a minimal impact on PLP expression until much later, when the expression level of QKI-6 in the transgenic animal significantly exceeds what is needed for normal myelination. Together, our results demonstrate that QKI-6 is the major isoform responsible for CNS myelination, which preferentially promotes MBP expression in oligodendrocytes.

The human homolog of the QKI gene affected in the severe dysmyelination "quaking" mouse phenotype: downregulated in multiple brain regions in schizophrenia.

OBJECTIVE: The authors sought to understand the origins of oligodendrocyte/myelin gene expression abnormalities in the brains of persons with schizophrenia. METHOD: Twelve cortical regions (Brodmann's areas 8, 10, 44, 46, 23/31, 24/32, 20, 21, 22, 36/28, 7, and 17) and three noncortical regions (caudate, hippocampus, and putamen) of 16 elderly schizophrenia patients and 14 matched comparison subjects were examined using 450 separate microarrays. The mRNA levels of QKI and its isoforms were then measured in a larger cohort by using quantitative real-time polymerase chain reaction (qPCR) in the cingulate cortex of schizophrenia subjects and matched comparison subjects. RESULTS: Expression of QKI mRNA was decreased in seven cortical regions and the hippocampus in the schizophrenia subjects. QKI gene expression deficits detected by microarray were validated by qPCR in the cingulate cortex, where the expression of isoforms QKI-5, QKI-6, and QKI-7 were profoundly perturbed in schizophrenia. CONCLUSIONS: Since QKI plays a fundamental role in oligodendrocyte differentiation and in myelination, its underexpression may be pivotal to, and upstream of, other myelin-associated gene expression abnormalities in schizophrenia. Given the role of QKI in determination of oligodendrocyte fate, these results not only confirm oligodendrocyte-related gene expression abnormalities in schizophrenia but suggest that the physiology of glial progenitor cells may be altered in schizophrenia.

QKI binds MAP1B mRNA and enhances MAP1B expression during oligodendrocyte development.

Microtubule-associated protein 1B (MAP1B) is essential for neural development. Besides the abundant expression in neurons, MAP1B recently was found in myelinating oligodendroglia. Moreover, MAP1B deficiency causes delayed myelin development, suggesting the functional importance of MAP1B in oligodendroglia. However, molecular mechanisms that control MAP1B expression in oligodendroglia remain elusive. We report here that MAP1B mRNA is markedly up-regulated in the oligodendroglia cell line CG4 upon induced differentiation, leading to elevated MAP1B protein production. A coordinated regulation of homeoprotein transcription factors was observed during CG4 cell differentiation, which recapitulates the regulation in neurons that promotes MAP1B transcription. Hence, transcriptional regulation of MAP1B appears to be a common mechanism in both neurons and oligodendroglia. In addition, we found posttranscriptional regulation of MAP1B mRNA by the selective RNA-binding protein QKI in oligodendroglia. The 3'UTR of MAP1B mRNA interacts with QKI, and oligodendroglia-specific QKI-deficiency in the quakingviable mutant mice resulted in reduced MAP1B mRNA expression. Moreover, RNAi-mediated QKI-knockdown caused destabilization of the MAP1B mRNA in CG4 cells. Furthermore, forced expression of exogenous QKI was sufficient for promoting MAP1B expression. Because QKI is absent in neurons, QKI-dependent stabilization of MAP1B mRNA provides a novel mechanism for advancing MAP1B expression specifically in oligodendroglia during brain development.

A new ENU-induced allele of mouse quaking causes severe CNS dysmyelination.

The mutant allelic series of the mouse quaking gene consists of the spontaneous quaking(viable) (qk(v)) allele, which is homozygous viable with a dysmyelination phenotype, and four ENU-induced alleles (qk(kt 1), qk(k2), qk(kt3/4), and qk(l-1)), which are homozygous embryonic lethal. Here we report the isolation of qk(e5), the first ENU-induced viable allele of quaking. Unlike qk(v)/qk(v), qk(e5)/qk(e5) animals have early-onset seizures, severe ataxia, and a dramatically reduced lifespan. Ultrastructural analysis of qk(e5)/qk(e5) brains reveals severe dysmyelination when compared with both wild-type and qk(v)/qk(v) brains. In addition, Calbindin detection in young adult qk(e5)/qk(e5) mice reveals Purkinje cell axonal swellings indicative of neurodegeneration , which is not seen in young adult qk(v)/qk(v) mice. Although the molecular defect in the qk(e5) allele is not evident by sequencing, protein expression studies show that qk(e5)/qk(e5) postnatal oligodendrocytes lack the QKI-6 and QKI-7 isoforms and have reduced QKI-5 levels. The oligodendrocyte developmental markers PDGF alpha R, NG 2, O4, CNP, and MBP are also present in the qk(e5)/qk(e5) postnatal brain although CNP and MBP levels are considerably reduced. Because the qk(v) allele is a large deletion that affects the expression of three genes, the new neurologic qk(e5) allele is an important addition to this allelic series.

Defining the breakpoints of the quaking(viable) mouse mutation reveals a duplication from a Parkin intron.

The quakingviable (qkv) mutant mouse shows a recessive neurological phenotype that includes central nervous system (CNS) dysmyelination, seizures, and tremor associated with voluntary movement. The molecular defect of qkv has been previously reported to be a spontaneous approximately 1 megabase (Mb) deletion in the proximal region of mouse chromosome 17 that occurred in the DBA mouse strain more than four decades ago. The mutation has recently been shown to affect three genes in the region: Quaking (qk), Parkin-coregulated gene (Pacrg), and Parkin. Here we determine the exact deletion breakpoints and demonstrate that the mutation is not just comprised of a approximately 1.1 Mb deletion, but also harbors a small 163 bp duplication fragment between the deletion breakpoints. Although the distal deletion breakpoint is within the fifth intron of the mouse Parkin gene, the duplicated sequence is derived from the sixth Parkin intron and shows positive transcriptional activity on a reporter gene in vitro. This complexity provides insight into a well-studied neurological mutant and may have a role in affecting the phenotype observed.

Target RNA motif and target mRNAs of the Quaking STAR protein.

Quaking viable (Qk(v)) mice have developmental defects that result in their characteristic tremor. The quaking (Qk) locus expresses alternatively spliced RNA-binding proteins belonging to the STAR family. To characterize the RNA binding specificity of the QKI proteins, we selected for RNA species that bound QKI from random pools of RNAs and defined the QKI response element (QRE) as a bipartite consensus sequence NACUAAY-N(1-20)-UAAY. A bioinformatic analysis using the QRE identified the three known RNA targets of QKI and 1,430 new putative mRNA targets, of which 23 were validated in vivo. A large proportion of the mRNAs are implicated in development and cell differentiation, as predicted from the phenotype of the Qk(v) mice. In addition, 24% are implicated in cell growth and/or maintenance, suggesting a role for QKI in cancer.

Reproductive and neurological Quaking(viable) phenotypes in a severe combined immune deficient mouse background.

The quaking(viable) (qkv) mutation, a spontaneous deletion of a multigenic region encompassing roughly 1 Mb at 5.9 cM on the proximal end of mouse chromosome 17, causes severe trembling in all homozygous animals and infertility in all homozygous males. Physiologically, quaking mice exhibit dysmyelination and postmeiotic spermatogenic arrest. Molecular defects in Qkv mice occur in the affected tissues, indicating the primary causes of these pathologies are cell autonomous. However, because both the reproductive and neurological defects are in immune-privileged sites and because some similar pathologies at both sites have been shown to be immune mediated, we tested whether the immune system participates secondarily in manifestation of Qkv phenotypes. The qkv mutation was bred into a severe combined immune-deficient mouse line (SCID; devoid of mature B and T cells) and penetrance of the neurological and the male sterile phenotypes was measured. Results showed that neither defect was ameliorated in the immune-deficient background. We conclude that the Qkv pathologies do not likely involve a B- or T-cell-dependent response against these immune-privileged sites.

QUAKING KH domain proteins as regulators of glial cell fate and myelination.

The quaking viable (qk(v)) mice have attracted attention because of their characteristic tremor caused by their dysmyelination. In the central nervous system, qk(v) mice fail to develop mature myelinating oligodendrocytes and display uncompacted myelin. The genetic defect in the qk(v) mice prevents the proper expression of alternatively spliced KH-type QKI RNA binding proteins. Thus qk(v) mice provide a unique animal model linking RNA binding proteins to defects in oligodendrocyte cell fate and myelination. The fact that QKI proteins are modified post-translationally makes them Signal Transduction Activiators of RNA (STAR) proteins. We have used a gain-of-function approach with the ectopic expression of the separate QKI isoforms using adenoviruses and retroviruses to determine their separate roles in cell fate and myelination. Herein, we discuss the recent advances in characterizing the QKI KH-type proteins as glial cell fate and myelin egulators.