BC1 RNA Protein Particles in Mouse Brain Contain Two Y-,H-Element-Binding Proteins, Translin and a 37 kDa Protein

Muramatsu, Toyojiro; Ohmae, Akiko; Anzai, Kentaro

doi:10.1006/bbrc.1998.8657

Cited by 42 publications

(36 citation statements)

References 26 publications

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“…62,63 Translin/Trax complexes are highly expressed in brain, where they are implicated in dendritic mRNA translation. 64 These trans splicing events are rare and although they produce novel fusion transcripts, they are low in abundance and translation products have yet to be documented. 57,61 DISC1 protein structure and conservation DISC1 alternative transcripts give rise to four predicted protein isoforms in humans.…”

Section: Disc1 Gene Structure and Evolutionmentioning

confidence: 99%

The DISC locus in psychiatric illness

et al. 2007

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The DISC locus is located at the breakpoint of a balanced t(1;11) chromosomal translocation in a large and unique Scottish family. This translocation segregates in a highly statistically significant manner with a broad diagnosis of psychiatric illness, including schizophrenia, bipolar disorder and major depression, as well as with a narrow diagnosis of schizophrenia alone. Two novel genes were identified at this locus and due to the high prevalence of schizophrenia in this family, they were named Disrupted-in-Schizophrenia-1 (DISC1) and Disrupted-in-Schizophrenia-2 (DISC2). DISC1 encodes a novel multifunctional scaffold protein, whereas DISC2 is a putative noncoding RNA gene antisense to DISC1. A number of independent genetic linkage and association studies in diverse populations support the original linkage findings in the Scottish family and genetic evidence now implicates the DISC locus in susceptibility to schizophrenia, schizoaffective disorder, bipolar disorder and major depression as well as various cognitive traits. Despite this, with the exception of the t(1;11) translocation, robust evidence for a functional variant(s) is still lacking and genetic heterogeneity is likely. Of the two genes identified at this locus, DISC1 has been prioritized as the most probable candidate susceptibility gene for psychiatric illness, as its protein sequence is directly disrupted by the translocation. Much research has been undertaken in recent years to elucidate the biological functions of the DISC1 protein and to further our understanding of how it contributes to the pathogenesis of schizophrenia. These data are the main subject of this review; however, the potential involvement of DISC2 in the pathogenesis of psychiatric illness is also discussed. A detailed picture of DISC1 function is now emerging, which encompasses roles in neurodevelopment, cytoskeletal function and cAMP signalling, and several DISC1 interactors have also been defined as independent genetic susceptibility factors for psychiatric illness. DISC1 is a hub protein in a multidimensional risk pathway for major mental illness, and studies of this pathway are opening up opportunities for a better understanding of causality and possible mechanisms of intervention. Molecular Psychiatry (2008) 13, 36-64; doi:10.1038/sj.mp.4002106; published online 2 October 2007 Keywords: schizophrenia; bipolar disorder; depression; DISC1; DISC2; mouse models Genetics of DISC1 discoverySt Clair et al. 1 first reported a Scottish family with a high loading of major mental illness, which cosegregates with a t(1;11) translocation. Long-term follow-up of this family over a period of 30 years has reported 87 family members, of whom 37 carry the translocation. 2 Of 29 individuals carrying the translocation, for whom psychiatric assessment was possible, 7 have a diagnosis of schizophrenia, 1 has a diagnosis of bipolar disorder and 10 cases of recurrent major depression were also reported. 2 Thus, 18 of 29 translocation carriers are diagnosed with major mental illness whereas none of...

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Section: Disc1 Gene Structure and Evolutionmentioning

confidence: 99%

The DISC locus in psychiatric illness

et al. 2007

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“…Translin is not required for the apical localization of hairy and wingless transcripts during embryogenesis: Human and mouse Translin proteins were found to associate with a variety of different so-called Y-and H-element-containing RNAs from brain and testes, including a-CAMKII, MBP, Tau, and Protamine mRNAs as well as noncoding RNAs such as BC1 (Han et al 1995a,b;Kobayashi et al 1998;Muramatsu et al 1998;Severt et al 1999). Translin has been suggested as being involved in the subcellular localization and translational regulation of its target RNAs (Morales et al 1998;Severt et al 1999;Yanget al 2003).…”

Section: Structure and Expression Of Drosophila Translin And Traxmentioning

confidence: 99%

“…Accordingly, it is thought to play a role in the subcellular transport and/or translational control of its target RNAs in these tissues (Han et al 1995a;Kobayashi et al 1998;Morales et al 1998;Muramatsu et al 1998;Wu and Hecht 2000;Yang et al 2003). Unlike Translin, Trax does not bind nucleic acids directly, but might be part of the RNA-or DNA-binding complex, thereby modulating the nucleic-acid-binding affinity of Translin (Chennathukuzhi et al 2001;Finkenstadt et al 2002;Gupta et al 2005).…”

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confidence: 99%

Functional Characterization of Drosophila Translin and Trax

Claußen¹,

Koch²,

Jin³

et al. 2006

Genetics

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The vertebrate RNA and ssDNA-binding protein Translin has been suggested to function in a variety of cellular processes, including DNA damage response, RNA transport, and translational control. The Translin-associated factor X (Trax) interacts with Translin, and Trax protein stability depends on the presence of Translin. To determine the function of the Drosophila Translin and Trax, we generated a translin null mutant and isolated a trax nonsense mutation. translin and trax single and double mutants are viable, fertile, and phenotypically normal. Meiotic recombination rates and chromosome segregation are also not affected in translin and trax mutants. In addition, we found no evidence for an increased sensitivity for DNA double-strand damage in embryos and developing larvae. Together with the lack of evidence for their involvement in DNA double-strand break checkpoints, this argues against a critical role for Translin and Trax in sensing or repairing such DNA damage. However, Drosophila translin is essential for stabilizing the Translin interaction partner Trax, a function that is surprisingly conserved throughout evolution. Conversely, trax is not essential for Translin stability as trax mutants exhibit normal levels of Translin protein.

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“…In the brain, translin binds CaMKII␣ and the untranslated RNA BC1 (Kobayashi et al, 1998;Severt et al, 1999;Wu and Hecht, 2000), dendritically localized RNAs that also associate with FMRP (Zalfa et al, 2003). Both proteins exhibit a somatodendritic distribution in neurons (Feng et al, 1997;Kobayashi et al, 1998;Muramatsu et al, 1998;Wu et al, 1999;Finkenstadt et al, 2000), shuttle between the nucleus and cytoplasm (Feng et al, 1997;Morales et al, 2002), interact with microtubules and motor proteins (Han et al, 1995a;Wu and Hecht, 2000;Ohashi et al, 2002;Antar et al, 2005), repress translation (Kwon and Hecht, 1993;Laggerbauer et al, 2001;Li et al, 2001;Yang et al, 2003), and may be involved in RNA interference (Caudy et al, 2002;Ishizuka et al, 2002;Wang et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Behavioral and Neurochemical Alterations in Mice Lacking the RNA-Binding Protein Translin

Stein¹,

Bergman²,

Fang³

et al. 2006

J. Neurosci.

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Synapse-specific local protein synthesis is thought to be important for neurodevelopment and plasticity and involves neuronal RNAbinding proteins that regulate the transport and translation of dendritically localized transcripts. The best characterized of these RNAbinding proteins is the fragile X mental retardation protein (FMRP). Mutations affecting the expression or function of FMRP cause fragile X syndrome in humans, and targeted deletion of the gene encoding FMRP results in developmental and behavioral alterations in mice. Translin is an RNA-binding protein that regulates mRNA transport and translation in mouse male germ cells and is proposed to play a similar role in neurons. Like FMRP, translin is present in neuronal dendrites, binds dendritically localized RNA, and associates with microtubules and motor proteins. We reported previously the production of viable homozygous translin knock-out mice, which demonstrate altered expression of multiple mRNA transcripts in the brain and mild motor impairments. Here, we report that translin knock-out mice also exhibit sex-specific differences in tests of learning and memory, locomotor activity, anxiety-related behavior, and sensorimotor gating, as well as handling-induced seizures and alterations in monoamine neurotransmitter levels in several forebrain regions. Similar behavioral and neurochemical alterations have been observed in mice lacking FMRP, suggesting that both proteins may act within the same neuronal systems and signaling pathways. Our results in mice indicate that mutations in translin may contribute to fragile X-like syndromes, mental retardation, attention deficit hyperactivity disorder, epilepsy, and autism spectrum disorders in humans.

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BC1 RNA Protein Particles in Mouse Brain Contain Two Y-,H-Element-Binding Proteins, Translin and a 37 kDa Protein

Cited by 42 publications

References 26 publications

The DISC locus in psychiatric illness

The DISC locus in psychiatric illness

Functional Characterization of Drosophila Translin and Trax

Behavioral and Neurochemical Alterations in Mice Lacking the RNA-Binding Protein Translin

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