FUS/TLS deficiency causes behavioral and pathological abnormalities distinct from amyotrophic lateral sclerosis
© Kino et al.; licensee BioMed Central. 2015
Received: 3 February 2015
Accepted: 30 March 2015
Published: 25 April 2015
FUS/TLS is an RNA-binding protein whose genetic mutations or pathological inclusions are associated with neurological diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and essential tremor (ET). It is unclear whether their pathogenesis is mediated by gain or loss of function of FUS/TLS.
Here, we established outbred FUS/TLS knockout mice to clarify the effects of FUS/TLS dysfunction in vivo. We obtained homozygous knockout mice that grew into adulthood. Importantly, they did not manifest ALS- or ET-like phenotypes until nearly two years. Instead, they showed distinct histological and behavioral alterations including vacuolation in hippocampus, hyperactivity, and reduction in anxiety-like behavior. Knockout mice showed transcriptome alterations including upregulation of Taf15 and Hnrnpa1, while they have normal morphology of RNA-related granules such as Gems.
Collectively, FUS/TLS depletion causes phenotypes possibly related to neuropsychiatric and neurodegenerative conditions, but distinct from ALS and ET, together with specific alterations in RNA metabolisms.
FUS/TLS is an RNA-binding protein associated with neurological diseases. Mutations in FUS/TLS cause familial amyotrophic lateral sclerosis (ALS), in which FUS/TLS protein is found in cytoplasmic inclusions [1,2]. In addition, inclusions containing this protein are also observed in people with sporadic ALS and a subset of individuals with frontotemporal lobar degeneration (FTLD) without FUS/TLS mutations [3,4]. More recently, FUS/TLS mutation was found in a family of hereditary essential tremor (ET) . The pathogenic mechanisms of these diseases remain unclear. Therefore, a major research interest is whether FUS/TLS-linked diseases are caused by gain or loss of function of FUS/TLS. Most FUS/TLS mutations in familial ALS are thought to disrupt a nuclear localization signal in the C-terminus, leading to facilitated formation of cytoplasmic stress granules as well as reduced nuclear function [6,7]. Transgenic mice overexpressing FUS/TLS recapitulate some ALS-like phenotypes . On the other hand, reduction in FUS/TLS leads to abnormality in Gems, nuclear granules marked by SMN1 that is involved in the assembly of small nuclear ribonucleoprotein particles and implicated in a motor neuron disease [9,10]. Primary hippocampal neurons from FUS/TLS-deficient embryos show abnormal dendritic spines . One critical piece of information that is still lacking is the phenotype of adult FUS/TLS knockout (KO) mice, as they die within a day after birth .
FUS/TLS regulates RNA metabolism, which includes transcription and post-transcriptional processing such as pre-mRNA splicing and mRNA trafficking, some of which are related to neuronal functions [13-16]. The N-terminal region of FUS/TLS forms reversible amyloid-like assemblies, which can be the molecular basis of the formation of RNA-containing granules, including neuronal granules [17,18]. Moreover, RNA metabolism has been highlighted as a potential common pathogenic pathway of ALS/FTLD, because genetic and pathological abnormalities of another RNA-binding protein, TDP-43, have been found in these diseases, as with FUS/TLS . Though previous studies identified transcriptome changes upon transient depletion of FUS/TLS or those in FUS/TLS deficient embryos [13-16], the effects of long-term FUS/TLS depletion on RNA metabolism have been still unclear.
In this study, we analyzed outbred homozygous FUS/TLS knockout (KO) mice to clarify the effects of FUS/TLS depletion on the central nervous system (CNS) in adults. We found abnormalities of the behavior and brain structure, but not ALS- or ET-like phenotypes, in the KO animals.
Materials and methods
TLS+/- mice  were maintained on the C57BL/6 J (B6) background. To obtain homozygous TLS KO mice, B6 TLS+/- mice were crossed with ICR mice. The F1 heterozygote mice were intercrossed. To maximize the survival of KO mice, some of the wild type or heterozygote littermates were removed from the cage. Male mice were used in experiments. All experiments with mice were approved by the Animal Experiment Committee of the RIKEN Brain Science Institute.
The experimental room was maintained in 12 hr light-12 hr dark periods (light period: 8:00 AM to 8:00 PM). Animals were tested blindly for their genotypes. For details of procedures, see Additional file 1: Supplemental Materials and Methods.
A mouse was placed in a plastic box attached with an accelerometer and allowed to move freely. The motion of the mouse was recorded for 1-5 minutes at a sampling rate of 1 kHz. Motion power percentage (MPP)  was calculated as (sum of amplitude at 10 ~ 20 Hz)/(sum of amplitude at 0 ~ 100 Hz) × 100.
Three animals were analyzed for each genotype at 8 weeks. 100 ng of total RNA was processed using WT Expression kit (Ambion) and WT Terminal Labeling kit (Affymetrix) and subjected to Mouse Exon 1.0 ST array (Affymetrix) according to the manufacture’s protocol. Dataset analysis was performed using AltAnalyze .
Quantitative PCR (qPCR)
Quantitative PCR analysis was performed using LightCycler 480 (Roche) and FastStart Universal SYBR Green Master (Roche). We used Gapdh for normalization.
PCR-based detection of alternative RNA processing
The sequence of primers is listed in Additional file 1: Supplemental Material. PCR products were resolved by agarose gel electrophoresis or 5-20% gradient polyacrylamide gel electrophoresis and stained with ethidium bromide or SYBR Gold (Molecular Probe).
Absence of ALS- or ET-like phenotypes in outbred FUS/TLS knockout mice
Importantly, the TLS-/- mice did not show apparent motor deficits, even at 90 weeks of age. The number of choline acetyltransferase-positive motor neurons in the spinal cord was not reduced in TLS-/- mice compared to TLS+/+ mice (Figure 1g and h). Furthermore, muscle histology of TLS-/- mice did not show apparent atrophic phenotypes (Figure 1i and j). We also measured tremor-like movement in TLS-/- mice. In a control experiment, wild-type mice were treated with harmaline, a widely used model of essential tremor. They showed a clear peak of amplitude at 10-18 Hz (Additional file 1: Figure S1a, Online Resource), reproducing previous results . In contrast, we did not detect any increase in the amplitude at this range in TLS-/- mice compared to TLS+/+ mice (Figure 1k and l). We also tested inbred TLS+/- mice on the B6 background but again did not observe tremor-like phenotypes (Additional file 1: Figure S1b, Online Resource). Thus, FUS/TLS depletion was not sufficient for inducing ALS- or ET-like phenotypes in vivo.
Behavioral and histological abnormalities in TLS-/- mice
Gene expression profile of TLS-/- mice
RNA processing and RNA-related granules in TLS-/- mice
We next analyzed RNA processing altered in the TLS-/- mice. Differentially regulated exons included previously known and unknown alternative processing (Figure 4d and Additional file 3: Table S2, Online Resource). We confirmed selected RNA processing alterations using gel-based PCR analysis or qPCR (Additional file 4: Table S3, Online Resource). As examples of differential cassette exon splicing, we confirmed exon inclusion of Ptk2b, Cnr1, App, Ogdh and Gria1 (Figure 4e and Additional file 1: Figure S4d, e, Online Resource). Recent reports suggested that FUS/TLS regulates alternative splicing of Mapt, encoding tau protein [26,27,15,14,16]. FUS/TLS-depleted embryonic brains and primary neurons show elevated inclusion of exon 9, also known as exon 10 in human, related to the "4-repeat" isoforms. We did not observe alteration in exon 9 splicing in our KO mice, as this exon was mostly included even in the WT (Figure 4e). Additionally, we found no significant alteration in the inclusion of exons 3/4 (Figure 4e). However, we observed an increase in the inclusion of exon 7B in KO mice (Figure 4e). This exon consists of 54 nucleotides (Additional file 1: Figure S4f, Online Resource) and its elevation has been reported in another study of FUS/TLS depletion in adult mice .
Next, we found changes in alternative usage of terminal exons (Additional file 4: Table S3, Online Resource). Differential expression of transcript isoforms was confirmed for Igbp1, Thra, Enpp5 and Inpp5f (Figure 4f and Additional file 4: Table S3, Online Resource). We also detected exons without previous annotations for RNA processing (Figure 4d). One of such examples was Gdpd3. We found relative down-regulation of 5’ regions of Gdpd3 in KO mice compared to the downstream region (Additional file 1: Figure S4b, Online Resource). 5’-RACE revealed that the 5’ region of Gdpd3 was shorter in TLS-/- mice (Additional file 1: Figure S4c, Online Resource), suggesting a role for FUS/TLS in transcriptional initiation. Collectively, we verified transcriptome changes in TLS-/- mice, consistent with the role of FUS/TLS as a regulator of RNA metabolism.
Defining FUS/TLS function in vivo is essential not only for understanding FUS/TLS-associated diseases but also for designing therapeutic strategies for them. We generated outbred TLS-/- mice, which grew into adulthood. In this TLS-/- strain, truncated FUS/TLS protein has been detected at very low levels in embryonic B cells . We did not detect accumulation of FUS/TLS in TLS-/- mice at 8 and 47 weeks, at the stages when they show phenotypical changes. Considering the aggregation-prone property of FUS/TLS lacking the C-terminus , the absence of pathological accumulation of FUS/TLS indicates that the protein expression from the mutant allele was too low to accumulate and supports that the phenotype of TLS-/- mice are mainly attributed to the loss of full-length FUS/TLS protein. Our mice provided several important findings summarized as follows.
(1) KO mice did not show ALS- or ET-like symptoms. The simplest interpretation is that loss of FUS/TLS function is not sufficient to cause ALS or ET, suggesting that FUS/TLS mutations in these diseases must involve some adverse effects distinct from simple loss of function. In line with this, transgenic mice overexpressing wild type FUS/TLS or its N-terminal fragment manifest ALS-like phenotypes together with pathological inclusions [8,28]. We do not rule out the possibility that loss of function of FUS/TLS causes ALS or ET depending on the genetic background or the timing of FUS/TLS depletion. If this is the case, however, our results would provide a therapeutic implication that ALS or ET caused by FUS/TLS depletion can be fully prevented by some genetic factors or compensatory responses, perhaps including upregulation of Taf15 and Ews. It is also possible that these disease are caused by the combinatorial effects of both gain and loss of function of FUS/TLS. (2) KO mice showed behavioral abnormalities, namely hyperactivity and reduced anxiety-related behavior, both of which were supported by multiple different tests. The hyperactivity of TLS-/- mice seemed dependent on habituation, a phenotype observed in human attention deficit/hyperactivity disorder (ADHD) . FUS/TLS is located in a region (16p11.2), where genomic copy number variations were found in ADHD individuals . (3) We also observed vacuole-like structures in the hippocampus of KO mice. Though vacuolation is known in some disease conditions represented by prion diseases, the underlying mechanisms are unclear. As the rim of vacuoles was stained with anti-MAP2, they might originate from dendrites or related structures. There are several genes whose mutation is associated with hippocampal vacuolation in mice (Prnp, Atrn, Mgrn1, Sp4, Gja1, Gjb6, Pnpla6), however, none of them showed altered mRNA expression in FUS/TLS KO mice. Therefore, FUS/TLS might be involved in a novel molecular pathway of vacuolation. Our results suggest that hippocampus is susceptible to FUS/TLS depletion. Though hippocampal vacuolation is not a typical pathological feature of FTLD, loss of FUS/TLS function might contribute to the abnormalities in FLTD hippocampus. In this regard, it is notable that FUS/TLS-positive inclusions in FTLD, but not those in ALS-FUS, are also positive for TAF15 and EWS , suggesting composite defects of the FUS/EWS/TAF15 protein family in FTLD-FUS that preclude functional compensation within the family. We noticed that the vacuolation was less frequent at later stages. At present, it is unclear whether the reduced frequency reflected recovery of the phenotype. Interestingly, there is an example of transient CA3 vacuolation, which was induced by Sp4 deficiency .
The transcriptome changes detected in our animals are important because some of these changes might be causally or consequentially related to the behavioral and pathological phenotypes. We found that adult TLS-/- mice show alterations in both gene expression and RNA processing, some of which were also identified previously and may represent reliable targets of FUS/TLS (Additional file 5: Table S4, Online Resource). We observed relatively small overlap of genes whose expression levels were altered in CNS regions analyzed (Figure 4a). Consistently, primary neurons from different CNS regions and glial cells show differential changes in their transcriptome when FUS/TLS is depleted . While reduction of Gems was reported in embryonic neurons from an independent strain of FUS/TLS KO mice , we observed a normal appearance of Gems. This discrepancy might be due to the cell types, conditions including genetic backgrounds, design of the mutant alleles, developmental stages, and the time span of FUS/TLS depletion in each study. We do not exclude the possibility that the trace amount of truncated FUS/TLS from the mutant allele in our mice prevented the abnormalities of Gems and some other RNA processing, which led to the viability of these mice. In any case, our results indicate that FUS/TLS may not be absolutely required for Gems. In this way, our mice provide unique opportunities to reveal the long-term effects of FUS/TLS depletion in adults.
In conclusion, our results demonstrate that deficiency of FUS/TLS leads to behavioral and pathological abnormalities that might be relevant to neuropsychiatric or neurodegenerative disorders, including FTLD. However, FUS/TLS KO mice did not develop phenotypes similar to ALS or ET. We also identified transcriptome changes caused by FUS/TLS depletion, which would be useful for future identification of biomarkers as well as molecular pathways reflecting FUS/TLS dysfunction in vivo.
Availability of supporting data
The data sets supporting the results of this article are included within the article and its additional files.
We would like to thank Ms. Itsuko Yamamoto and Ms. Tomoko Yoda for animal maintenance, Dr. Kazuyuki Yamada for advices, the Research Resource Center staff of RIKEN Brain Science Institute for DNA sequencing and microarray processing. This work was supported by Grants-in-Aid for Scientific Research from The Ministry of Education, Culture, Sports, Science and Technology to Y.K. (23791007 and 25461299) and to N.N. (22110004, 22240037, 24659436, 25253066), by CREST from JST for N.N., and by Grant-in-Aid for the Research on Measures for Ataxic Diseases from the Ministry of Health, Welfare and Labor to N.N.
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