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The STAR Protein QKI-6 Is a Translational Repressor

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The STAR Protein QKI-6 Is a Translational Repressor The STAR protein QKI-6 is a translational repressor Lisa Saccomanno*, Carrie Loushin†, Eric Jan*, Eric Punkay*, Karen Artzt†, and Elizabeth B. Goodwin*‡ *Department of Cell and Molecular Biology and the Lurie Cancer Center, Northwestern University Medical School, Chicago, IL 60611; and †Institute of Cellular and Molecular Biology, Department of Microbiology, University of Texas, Austin, TX 78712 Edited by Judith Kimble, University of Wisconsin, Madison, WI, and approved August 16, 1999 (received for review January 20, 1999) The signal transduction and activation of RNA (STAR) family of repressing tra-2 translation (9). The TGE control is a conserved RNA-binding proteins, whose members are evolutionarily con- process that is present in nematodes and mammals (14), raising served from yeast to humans, are important for a number of the possibility that other STAR family members act through developmental decisions. For example, in the mouse, quaking TGE-like elements to control translation. We addressed this idea proteins (QKI-5, QKI-6, and QKI-7) are essential for embryogenesis by asking whether the mouse quaking proteins (QKI) are TGE- and myelination , whereas a closely related protein in Caenorhab- dependent translational regulators. ditis elegans, germline defective-1 (GLD-1), is necessary for germ- The qk gene produces at least three major transcripts that are line development. Recently, GLD-1 was found to be a translational 5(qkI-5),6(qkI-6), and 7 (qkI-7) kb long (2). The three repressor that acts through regulatory elements, called TGEs (for transcripts produce very similar proteins, QKI-5, QKI-6, and tra-2 and GLI elements), present in the 3؅ untranslated region of the QKI-7, respectively, that differ only at the carboxyl terminus. All sex-determining gene tra-2. This gene promotes female develop- three proteins contain the identical KH RNA-binding domain ment, and repression of tra-2 translation by TGEs is necessary for and QUA1 and QUA2 domains. Northern blot analyses indicate the male cell fates. The finding that GLD-1 inhibits tra-2 translation that qkI-5 mRNA is the major form present in early embryos, and raises the possibility that other STAR family members act by a that qkI-6 and qkI-7 mRNA are found in late development when similar mechanism to control gene activity. Here we demonstrate, myelination begins (16). Immunocytochemistry experiments in- both in vitro and in vivo, that QKI-6 functions in the same manner dicate that QKI proteins are expressed in oligodendrocytes and as GLD-1 and can specifically bind to TGEs to repress translation of astrocytes in the central nervous system as well as Schwann cells reporter constructs containing TGEs. In addition, expression of in the peripheral nervous system. QKI-5 is nuclear, although it QKI-6 in C. elegans wild-type hermaphrodites or in hermaphrodites shuttles between the nucleus and cytoplasm, whereas QKI-6 and that are partially masculinized by a loss-of-function mutation in the QKI-7 are predominantly cytoplasmic (16, 17). sex-determining gene tra-3 results in masculinization of somatic Recessive viable mutations in quaking (qkv) result in hypomy- tissues, consistent with QKI-6 repressing the activity of tra-2. These elination, and as a result the qkv homozygotes develop a rapid results strongly suggest that QKI-6 may control gene activity by tremor by postnatal day 10. Homozygotes also suffer chron- operating through TGEs to regulate translation. In addition, our ic͞tonic seizures (18). The myelin deficiency is most pronounced data support the hypothesis that other STAR family members may in the brain, less in the spinal cord, and even less in the peripheral also be TGE-dependent translational regulators. nervous system (19). In the qkv allele, QKI-6 and QKI-7 are absent from oligodendrocytes and Schwann cells (16), possibly quaking ͉ myelination ͉ mouse ͉ translation control ͉ tra-2 and GLI explaining the tremors in mutant animals. Other qk alleles, element (TGE) embryonic lethal mutations induced by ethylnitrosourea (qkkt4), have been isolated (20–22). The terminal phenotype is one of he STAR family of RNA-binding proteins is required for a arrested growth with generalized abnormalities by embryonic Tnumber of important developmental decisions in both ver- day 9, but the precise cause of lethality is not known (3). The tebrates and invertebrates (1). STAR family members contain a mice die more than 10 days before myelination begins, indicating conserved KH domain as well as two conserved domains called that QKI proteins may affect multiple cellular processes. BIOLOGY QUA1 and QUA2. STAR proteins are necessary for embryo- In this paper, we find that like GLD-1, the QKI-6 protein can DEVELOPMENTAL genesis and myelination in the mouse (2, 3), muscle development act through TGEs to repress translation. This finding is sup- in Drosophila (4, 5), notochord differentiation in Xenopus (6), ported by the observation that QKI-6 specifically binds TGEs, and germ-line development in Caenorhabditis elegans (7, 8). represses translation of reporter RNAs both in vivo and in vitro, Although over 30 STAR family members have been identified, and promotes the fate of male cells in C. elegans. Our findings for most, it is not clear how they function to regulate gene indicate that a number of STAR family proteins may control activity. gene expression by repressing translation through TGEs. Recently, GLD-1 was shown to inhibit the translation of the Methods C. elegans sex-determining gene tra-2 (9). C. elegans has two sexes: hermaphrodites and males. Hermaphrodites are essen- General Procedures and Strains. Routine maintenance was as tially female animals that make sperm and then oocytes. tra-2 is described in ref. 23. All strains were raised at 20°C unless required for female development and is predicted to encode a otherwise noted. The following mutant alleles were used in this large transmembrane protein, called TRA-2A, that is necessary study: LGII, tra-2(e2020 gf) (15); LGIV, unc-24(e138)fem- ͞ to inhibit downstream male determinants (10–12). GLD-1 is 3(e1996lf); LGIV, tra-3(e1107) nT1 (24). The balancer nT1 germ line specific and plays multiple roles in hermaphrodite (previously called DnT1) suppresses recombination over much germ cell development. In the hermaphrodite, GLD-1 is essen- of chromosome IV (25). tial for oogenesis (7) and is necessary for hermaphrodite sper- matogenesis and inhibition of premeiotic proliferation (7). This paper was submitted directly (Track II) to the PNAS office. tra-2 is translationally regulated by two elements, called TGEs ␤ ␤ Ј Ј (for tra-2 and GLI elements), located in the 3Ј untranslated Abbreviations: TGE, tra-2 and GLI element; -gal, -galactosidase; 3 UTR, 3 untranslated Ј region; STAR, signal transduction and activation of RNA; GLD-1, germline defective-1; tra-2, region (3 UTR) (13, 14). Translational repression of tra-2 is transformer. required for hermaphrodite spermatogenesis (13, 15). GLD-1 ‡To whom reprint requests should be addressed. E-mail: [email protected]. specifically binds the TGEs and represses translation of TGE- The publication costs of this article were defrayed in part by page charge payment. This containing RNAs both in vivo and in vitro (9). These findings article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. suggest that GLD-1 controls hermaphrodite spermatogenesis by §1734 solely to indicate this fact. PNAS ͉ October 26, 1999 ͉ vol. 96 ͉ no. 22 ͉ 12605–12610 Downloaded by guest on September 26, 2021 RNA Gel Shift Analysis. A construct encoding the entire QKI-6 or TTTTGGAACCAAATTCTCGCCCTATAGTGAGTCGTA- a mutant QKI-6 that carries the qkkt4 mutation (amino acid TTA-3Ј. number 48 has been changed from glutamic acid to glycine) with EJ-19: 5Ј-TGTGTTCAGAAAACTAGGCAGGAAAGTA- an amino-terminal His tag (His-QKI-6 or His-QKkt4), were GGAAAAGATCTGTTAATCGCCCTATAGTGAGTCGTA- expressed in bacteria and purified by using the His-Binding TTA-3Ј. Buffer Kit (Novagen) (17). RNA gel shifts were performed as EJ-24: 5Ј-GGAAGGATAGAAACCCCTTAGGAAATGC- described (13). 32P-labeled and unlabeled tra-2(ϩ) and tra- GATCTGTGATGGATGAGATTCCCTCGCCCTATAGTG- 2(Ϫ108) 3ЈUTR probes were made by standard methods as AGTCGTATTA-3Ј. described (26). Small 32P-labeled RNAs (EBG-9, EBG-11, EJ- EJ-32: 5Ј-TACAAGATCTGTGTTCCTAGGCAGGAAAG- 19, EJ-32, EJ-35, EJ-38, EMP-9, and EMP-10) were produced by TAGGAAACACAGATCTGTTCGCCCTATAGTGAGTCG- using the method of Milligan and Uhlenbeck (27). See below for TATTA-3Ј. sequences. EJ-35: 5Ј-GAATTCTCGAGTACAAGATCTGTGTTCCT- AGGCAGGAAAGTAGGAAAGTGAGATCTGTTCGCCC- Transgenic Analysis. hsp::QKI-6 (also called pBG102) was made by TATAGTGAGTCGTATTA-3Ј. amplifying the qkI-6 coding region by PCR with primers EMP-7 and EJ-38: 5Ј-TGCAGCTCCCCCAATTTTTCTGGAAGGAT- EMP-8. The PCR product was cut with SalI and cloned into the AGAAACCCCTTAGGAAATGCGATCTGTGATGGATG- same site of pBG518. pBG518 contains the C. elegans-inducible AGATTCCCTCGCCCTATAGTGAGTCGTATTA-3Ј. heat shock promoter, hsp16.41, and the C. elegans unc-54 3ЈUTR (9). The construction of pBG3 [lacZ::Ce-tra-2(-32)3ЈUTR] and Results and Discussion pBG4 [lacZ::Ce-tra-2(Ϫ60)3ЈUTR] are described elsewhere (28). To test whether other STAR proteins, like GLD-1, are transla- Transgenic C. elegans animals were generated by using stan- tional repressors, we asked whether the murine QKI proteins dard methods (29): 25 ng͞␮lofhsp::QKI-6 with 50 ng͞␮lof could control translation in a TGE-dependent manner. By using emb-9::GFP were injected into animals carrying either RNA gel
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