2020. 2. 19. 18:57ㆍ카테고리 없음
Abstract Background: Tightly regulated pathways maintain the balance between proliferation and differentiation within stem cell populations. In Caenorhabditis elegans, the germline is the only tissue that is maintained by stem-like cells into adulthood.
In the current study, we investigated the role played by a member of the Homeodomain interacting protein kinase (HIPK) family of serine/threonine kinases, HPK-1, in the development and maintenance of the C. Elegans germline.
Results: We report that HPK-1 is required for promotion of germline proliferation during development and into adulthood. Additionally, we show that HPK-1 is required in the soma for regulation of germline proliferation. We also show that HPK-1 is a predominantly nuclear protein expressed in several somatic tissues including germline-interacting somatic cells. Conclusions: Our observations are consistent with a conserved role for HIPKs in the control of cellular proliferation and identify a new context for such control in germ cell proliferation. Developmental Dynamics 242:1250–1261, 2013. © 2013 Wiley Periodicals, Inc. INTRODUCTION Gamete production requires a balance between proliferation and differentiation in the germline stem cell population.
In many animals, germline stem cells proliferate within an anatomical niche, with signals from the niche regulating this balance. Since favouring proliferation over differentiation may cause tumorigenesis and differentiation without self-renewal can deplete the tissue leading to infertility, understanding the signals that influence proliferation and differentiation within the germline is of interest. The germline of Caenorhabditis elegans is a useful system for studying how the balance between proliferation and differentiation is maintained (Hubbard, ). Elegans germline consists of two gonad arms each with a closed distal end at which the progenitor cell pool is maintained. Germline stem cells are located nearest to the distal tip cell (DTC), which caps the proliferative region, also known as the mitotic region, and extends projections to encompass it (Crittenden et al., ) (Fig. Five pairs of gonadal sheath cells form another important germline-associated somatic tissue that plays critical roles in germline development and maintenance (McCarter et al.,; Hall et al., ).
Establishment and maintenance of the mitotic region are predominantly governed by GLP-1/Notch signalling from the DTC (Kimble and Crittenden,; Hubbard, ). The DTC expresses DSL (Delta/Serrate/LAG-2) ligands, LAG-2 and APX-1, on its surface (Henderson et al.,; Nadarajan et al., ). These ligands are recognised by neighbouring germ cells expressing the GLP-1 receptor, which is then thought to activate proliferation-promoting genes by entering the nucleus and binding the LAG-1 transcription factor complex (Austin and Kimble,; Crittenden et al., ). Additionally, Notch signalling prevents meiosis in the most distal part of the gonad through inhibition of GLD proteins (GLD-1, GLD-2, and GLD-3) and NOS-3 (Kadyk and Kimble,; Crittenden et al., ). This is achieved through FBF-1 and FBF-2, two PUF (Pumilio and FBF) RNA-binding proteins that repress GLDs posttranscriptionally (Crittenden et al.,; Eckmann et al., ).
Together these proteins form a complex regulatory network to drive proliferation and inhibit differentiation in the mitotic region. Once cells are no longer under the influence of GLP-1/Notch signalling, they start to transition into meiosis. The transition zone (TZ) is characterised by crescent-shaped nuclear morphology (Kimble and Crittenden, ). In addition to GLP-1/Notch signalling, insulin/IGF-like receptor (IIR) signalling and uncharacterised signals from the gonadal sheath cells are also required for the proper establishment of the progenitor cell pool in the germline (McCarter et al.,; Korta and Hubbard,; Michaelson et al., ). The germline of C. Elegans consists of two U-shaped gonad arms.
The distal tip cell (DTC) is on the right in the gonad schematic. From there, cells move through different phases of maturation towards the proximal region of the germline where they are fertilised. Anatomical positions of the five pairs of gonadal sheath cells along the germline are shown. Homeodomain interacting protein kinases (HIPKs) are a family of serine/threonine protein kinases evolutionarily conserved within metazoa (Kim et al.,; Rinaldo et al., ).
There are four mammalian members (HIPK1–4) with HIPK2 being the best characterised. HIPKs interact with and regulate the activity of numerous cellular proteins including several transcription factors and cofactors (Rinaldo et al., ). They have been implicated in the control of a range of cellular pathways to regulate various processes including the DNA damage response, tissue specification, and proliferation (Rinaldo et al.,; Zhang et al.,; Iacovelli et al.,; Poon et al., ).
There is some evidence that HIPK proteins control proliferation, although the findings are not entirely uniform, with varied observations depending on the organism and tissues studied. For example, inhibition of cell proliferation by HIPK2 was first illustrated in rat thyroid cells after overexpression of HIPK2 resulted in blocking of the cell cycle at the G2/M phase (Pierantoni et al., ). In contrast, it was later shown that Hipk1 Hipk2–deficient mice embryos showed reduced proliferation in the neural tube suggesting that HIPKs could, in some contexts, promote proliferation (Isono et al., ). Furthermore Hipk2 −/− newborn mice are smaller in size compared with their wild type littermates and Hipk2 −/− mouse embryonic fibroblasts (MEFs) exhibit reduced proliferation (Trapasso et al., ).
Drosophila Hipk has also been shown to be essential for promotion of eye growth, proliferation, and patterning (Lee et al., ). In addition excess expression of Hipk in Drosophila leads to overgrowth of adult tissues (Lee et al.,; Chen and Verheyen,; Poon et al., ). We were interested in clarifying the in vivo functions of this family of proteins and so began an analysis of the sole nematode member of this family, HPK-1. Although animals carrying a hpk-1 mutation have previously been studied (Raich et al., ), no obvious phenotypes were noted. Here we report that HPK-1 is a predominantly nuclear protein expressed in many somatic tissues. Mutation of hpk-1 results in reduced brood size and reduced proliferation of the germline. We also find that this effect is cell non-autonomous, with HPK-1 required in the soma for robust germline proliferation.
RESULTS hpk-1(pk1393) Mutants Display Reduced Germline Proliferation The nematode protein HPK-1 shares high sequence homology with vertebrate HIPKs, particularly within the kinase domain. In this functionally important domain, HPK-1 displays 83, 80, and 82% identity with human HIPK1, HIPK2, and HIPK3, respectively.
There are three identified isoforms of hpk-1 in C. The longest isoform hpk-1 (annotated as F20B6.8b in WormBase) consists of eight exons (Fig. To investigate if HPK-1 is required for any aspect of germline development or maintenance, we utilised the mutant hpk-1(pk1393). This allele is a deletion that removes the majority of the kinase domain including the predicted active site in all three identified isoforms. By removing the putative catalytic domain from this kinase, it is likely that this allele is null (Fig. hpk-1 mutants display reduced brood size.
A: Schematic representation of the hpk-1 locus. Black boxes indicate exons, black lines represent introns, and the white box represents the 5′ untranslated region. The deletion in the pk1393 allele removes the majority of the kinase domain. B: Schematic representation of the HPK-1 protein (top) and the putative truncated version encoded by allele pk1393 (bottom). The kinase domain is indicated in white and the novel segment encoded as a result of a frameshift in allele pk1393 is shown in black.
C: The brood size of wild type animals and hpk-1(pk1393) mutants was measured over the reproductive period of each animal. N = 10–16 broods. HPK-1 is required for robust germline proliferation. A: A single layer of the z-stack showing the morphology of the distal end of the gonad arms stained with DAPI for wild type animals (top) and hpk-1(pk1393) mutants (bottom) at three different growth stages investigated, DTC is on the right and dashed line indicates the start of the transition zone (TZ). Scale bar = 50 μm.
B: Length of the mitotic zone at the adult molt stage was measured by staining extruded gonads with DAPI and determining the number of cell diameters to the TZ. Shown are averages of three independent experiments, n= 10–20 gonads scored/experiment. C: Size of the mitotic region was measured by the total number of cells at three different stages in wild type animals and hpk-1(pk1393) mutants, n= 4–19 gonads scored. D: The number of PH3-positive cells was scored at L4 and adult molt stage in wild type animals and hpk-1(pk1393) mutants using immunofluorescence (anti-PH3) on dissected gonads. Shown are averages of three independent experiments, n= 10–20 gonads scored/experiment. Expression of HPK-1 as analysed with HPK-1::mCherry transgene. A: X chromosome region covering the fosmid WRM0636bF06 within which the hpk-1 gene is contained (non-coding RNAs omitted from the schematic).
MCherry was inserted in frame at the C terminus using recombineering as per Tursun et al. B: Fluorescence (left) and DIC (right) micrographs of adult hermaphrodites expressing HPK-1::mCherry under normal conditions.
Fluorescence was detected in the nucleus of cells in the head (i), gonadal sheath cells (ii, with one enlarged nucleus inset), and DTC (dissected gonad arm, iii). C: Fluorescence (left) and bright field (right) micrographs of adult hermaphrodites expressing HPK-1::mCherry after heat shock treatment; head (i), gonadal sheath cells (ii) and hypodermis (iii). Scale bar = 20 μm. In mammals, HIPK2 levels are tightly regulated, with stabilisation of HIPK2 occurring in response to genotoxic stress (Winter et al., ).
To examine whether stress also alters nematode HPK-1 levels, we exposed animals carrying the hpk-1::mcherry reporter transgene to heat shock. The level of expression of HPK-1 after heat shock treatment was increased in many nuclei in the head and in the gonadal sheath cells, where robust nuclear mcherry fluorescence was readily observed (Fig. C, i and ii). Furthermore, additional HPK-1::mCherry-expressing cells were apparent after heat shock (Fig. Together this analysis demonstrates that HPK-1 is a predominantly nuclear protein that it is broadly expressed in somatic tissues and is induced under conditions of heat stress. The Reduced Proliferation Phenotype of the hpk-1 Mutant is Rescued by HPK-1::mCherry Transgene We have observed that hpk-1 mutants display a reduction in germline proliferation but did not detect germline expression of the HPK-1::mCherry reporter. While it is possible that HPK-1 levels in the germline are below the threshold for detection, the absence of apparent germline expression suggested that HPK-1 may not be acting cell autonomously to control germline proliferation.
In order to examine if HPK-1 is required in the germline and/or soma to regulate germline proliferation, we first attempted to rescue the reduced proliferation phenotype of the hpk-1 mutant with two different HPK-1::mCherry-expressing transgenes. For this purpose, both the described integrated fosmid transgene expressing HPK-1::mCherry (Ishpk-1(+)) and an extrachromosomal array containing this same recombineered fosmid (Exhpk-1(+)) were introduced into the hpk-1(pk1393) mutant background. Gonads extruded from lines expressing HPK-1::mCherry in a wild type background are of expected size and show no major abnormalities (Fig.
Gonads extruded from the hpk-1(pk1393) mutants are drastically smaller than the wild type gonads and this is reversed when transgenic HPK-1::mCherry is introduced into the hpk-1(pk1393) strain (Fig. Mutants of hpk-1(pk1393) carrying each of the two transgenes were analysed for proliferation phenotypes by examining the brood size and the number of PH3-positive cells. Brood size of hpk-1(pk1393) mutants (148, n = 10) was rescued to wild type levels with the Ishpk-1(+) transgene (277, n= 15) and to a lesser extent with the Exhpk-1(+) transgene (238, n= 22) (Fig.
Similarly, both transgenes rescued the PH3-positive cell number; strains with either transgene in the hpk-1 mutant background display wild type levels of PH3-positive cells (1.6 in hpk-1 mutant vs. 3.4 and 3.6 with strains carrying (Ishpk-1) and (Exhpk-1) in the same background, respectively, and 3.9 in wild type) (Fig.
While these data suggest that expression of HPK-1::mcherry can rescue the germline proliferation defect of hpk-1(pk1393) mutants, the fosmid-based transgenes used in these assays contain coding regions in addition to hpk-1 (Fig.A), and a contribution of these to the observed rescue can not be excluded. HPK-1::mCherry rescues the germline proliferation phenotype of the hpk-1(pk1393) mutant. A: Dissected gonad arms from first day adults were stained with DAPI to highlight nuclear morphology; distal end of the germline is on the right-hand side. Scale bar = 50 μm. B, C: Brood size (B, n= 10–25 broods scored; WT and hpk-1(pk1393) data as shown in Fig.
C) and the number of PH3-positive cells (C, n= 8–29 gonads scored per experiment/per strain; averages are representative of two individual experiments) were scored to check for rescue of the hpk-1(pk1393) mutant phenotype with integrated (Ishpk-1(+) and extrachromosomal (Exhpk-1) HPK-1::mCherry transgenes. HPK-1 knockdown in the soma results in reduced germline proliferation. RNAi by feeding was utilised to knock down hpk-1 transcript levels in wild type animals and rrf-1(pk1417) and ppw-1(pk2505) mutants. A: Representative images of dissected gonads after RNAi stained with DAPI (top) and PH3 antibody (bottom). Distal end is on the right-hand side. Scale bar = 50 μm. B: Number of PH3-positive cells was quantified after hpk-1 RNAi in each strain.
Data have been grouped from three (WT) or two rrf-1(pk1417) and ppw-1(pk2505) independent experiments, n= 11–24 gonads/experiment/strain. N.s.= not significant;. P.
DTC formation may be compromised in hpk-1 mutants. A: Micrographs showing gonadal sheath cell marker plim-7::gfp expression (top) and corresponding bright field (bottom) in wild type and hpk-1(pk1393) mutant background. Distal end is on the right-hand side. Scale bar= 50 μm.
B: Mean fluorescence intensity was quantified using Image J software. Shown are averages of 20 animals per genotype. C: Micrographs showing whole animals with two (top) and one (bottom) DTCs expressing plag-2::gfp. Scale bar= 200 μm. D: The percentage of animals with either two or one GFP-expressing DTC was quantified at L4 stage and adult molt in wild type and hpk-1(pk1393) mutant.
Shown are averages of three independent experiments, n= 24–200 animals scored/experiment. N.s.= not significant,. P. cep-1 null mutation does not change the extent of the hpk-1 mutant proliferation phenotype. Length of the mitotic zone ( A) and the number of PH3-positive cells ( B) was measured at the adult molt stage.
Shown are averages of three independent experiments for wild type animals, hpk-1(pk1393), cep-1(gk138) and hpk-1(pk1393); cep-1(gk138) double mutants. N= 10 gonads scored/experiment. Austin J, Kimble J. Glp-1 is required in the germ line for regulation of the decision between mitosis and meiosis in C. Cell 51: 589– 599. Blelloch R, Anna-Arriola SS, Gao D, Li Y, Hodgkin J, Kimble J. The gon-1 gene is required for gonadal morphogenesis in Caenorhabditis elegans.
Dev Biol 216: 382– 393. Chen J, Verheyen EM. Homeodomain-interacting protein kinase regulates yorkie activity to promote tissue growth. Curr Biol 22: 1582– 1586. Cheng Y, Al-Beiti MA, Wang J, Wei G, Li J, Liang S, Lu X. Correlation between homeodomain-interacting protein kinase 2 and apoptosis in cervical cancer.
Mol Med Rep 5: 1251– 1255. Choi CY, Kim YH, Kim YO, Park SJ, Kim EA, Riemenschneider W, Gajewski K, Schulz RA, Kim Y. Phosphorylation by the DHIPK2 protein kinase modulates the corepressor activity of Groucho. J Biol Chem 280: 21427– 21436. Crittenden SL, Troemel ER, Evans TC, Kimble J.
GLP-1 is localized to the mitotic region of the C. Elegans germ line. Development 120: 2901– 2911. Crittenden SL, Bernstein DS, Bachorik JL, Thompson BE, Gallegos M, Petcherski AG, Moulder G, Barstead R, Wickens M, Kimble J. A conserved RNA-binding protein controls germline stem cells in Caenorhabditis elegans. Nature 417: 660– 663.
Crittenden SL, Leonhard KA, Byrd DT, Kimble J. Cellular analyses of the mitotic region in the Caenorhabditis elegans adult germ line. Mol Biol Cell 17: 3051– 3061. D'Orazi G, Cecchinelli B, Bruno T, Manni I, Higashimoto Y, Saito S, Gostissa M, Coen S, Marchetti A, Del Sal G, Piaggio G, Fanciulli M, Appella E, Soddu S.
Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis. Nat Cell Biol 4: 11– 19. Derry WB, Bierings R, van Iersel M, Satkunendran T, Reinke V, Rothman JH. Regulation of developmental rate and germ cell proliferation in Caenorhabditis elegans by the p53 gene network. Cell Death Differ 14: 662– 670.
Eckmann CR, Crittenden SL, Suh N, Kimble J. GLD-3 and control of the mitosis/meiosis decision in the germline of Caenorhabditis elegans. Genetics 168: 147– 160.
Gao MX, Liao EH, Yu B, Wang Y, Zhen M, Derry WB. The SCF FSN-1 ubiquitin ligase controls germline apoptosis through CEP-1/p53 in C. Cell Death Differ 15: 1054– 1062. Hall DH, Winfrey VP, Blaeuer G, Hoffman LH, Furuta T, Rose KL, Hobert O, Greenstein D.
Ultrastructural features of the adult hermaphrodite gonad of Caenorhabditis elegans: relations between the germ line and soma. Dev Biol 212: 101– 123. Henderson ST, Gao D, Lambie EJ, Kimble J.
Lag-2 may encode a signaling ligand for the GLP-1 and LIN-12 receptors of C. Development 120: 2913– 2924.
Hendzel MJ, Wei Y, Mancini MA, Van Hooser A, Ranalli T, Brinkley BR, Bazett-Jones DP, Allis CD. Mitosis-specific phosphorylation of histone H3 initiates primarily within pericentromeric heterochromatin during G2 and spreads in an ordered fashion coincident with mitotic chromosome condensation. Chromosoma 106: 348– 360. Hofmann TG, Moller A, Sirma H, Zentgraf H, Taya Y, Droge W, Will H, Schmitz ML. Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2. Nat Cell Biol 4: 1– 10.
Hubbard EJ. Caenorhabditis elegans germ line: a model for stem cell biology. Dev Dyn 236: 3343– 3357.
Iacovelli S, Ciuffini L, Lazzari C, Bracaglia G, Rinaldo C, Prodosmo A, Bartolazzi A, Sacchi A, Soddu S. HIPK2 is involved in cell proliferation and its suppression promotes growth arrest independently of DNA damage. Cell Prolif 42: 373– 384.
Isono K, Nemoto K, Li Y, Takada Y, Suzuki R, Katsuki M, Nakagawara A, Koseki H. Overlapping roles for homeodomain-interacting protein kinases hipk1 and hipk2 in the mediation of cell growth in response to morphogenetic and genotoxic signals.
Mol Cell Biol 26: 2758– 2771. Jin Y, Ratnam K, Chuang PY, Fan Y, Zhong Y, Dai Y, Mazloom AR, Chen EY, D'Agati V, Xiong H, Ross MJ, Chen N, Ma'ayan A, He JC. A systems approach identifies HIPK2 as a key regulator of kidney fibrosis. Nat Med 18: 580– 588.
Kadyk LC, Kimble J. Genetic regulation of entry into meiosis in Caenorhabditis elegans. Development 125: 1803– 1813. Kamath RS, Martinez-Campos M, Zipperlen P, Fraser AG, Ahringer J. Effectiveness of specific RNA-mediated interference through ingested double-stranded RNA in Caenorhabditis elegans. Genome Biol 2: research0002.1– 0002.10.
Kim YH, Choi CY, Lee SJ, Conti MA, Kim Y. Homeodomain-interacting protein kinases, a novel family of co-repressors for homeodomain transcription factors. J Biol Chem 273: 25875– 25879. Kimble J, Crittenden SL. Germline proliferation and its control. WormBook 1– 14.
Kimble J, Crittenden SL. Controls of germline stem cells, entry into meiosis, and the sperm/oocyte decision in Caenorhabditis elegans. Annu Rev Cell Dev Biol 23: 405– 433. Korta DZ, Hubbard EJ. Soma-germline interactions that influence germline proliferation in Caenorhabditis elegans. Dev Dyn 239: 1449– 1459.
Kumsta C, Hansen M. Elegans rrf-1 mutations maintain RNAi efficiency in the soma in addition to the germline. PLoS One 7: e35428. Lee W, Andrews BC, Faust M, Walldorf U, Verheyen EM. Hipk is an essential protein that promotes Notch signal transduction in the Drosophila eye by inhibition of the global co-repressor Groucho.
Dev Biol 325: 263– 272. Lee W, Swarup S, Chen J, Ishitani T, Verheyen EM. Homeodomain-interacting protein kinases (Hipks) promote Wnt/Wg signaling through stabilization of beta-catenin/Arm and stimulation of target gene expression. Development 136: 241– 251. McCarter J, Bartlett B, Dang T, Schedl T.
Soma-germ cell interactions in Caenorhabditis elegans: multiple events of hermaphrodite germline development require the somatic sheath and spermathecal lineages. Dev Biol 181: 121– 143. Michaelson D, Korta DZ, Capua Y, Hubbard EJ. Insulin signaling promotes germline proliferation in C.
Development 137: 671– 680. Miyabayashi T, Palfreyman MT, Sluder AE, Slack F, Sengupta P.
Expression and function of members of a divergent nuclear receptor family in Caenorhabditis elegans. Dev Biol 215: 314– 331. Nadarajan S, Govindan JA, McGovern M, Hubbard EJ, Greenstein D. MSP and GLP-1/Notch signaling coordinately regulate actomyosin-dependent cytoplasmic streaming and oocyte growth in C. Development 136: 2223– 2234. Navarro RE, Shim EY, Kohara Y, Singson A, Blackwell TK. Cgh-1, a conserved predicted RNA helicase required for gametogenesis and protection from physiological germline apoptosis in C.
Development 128: 3221– 3232. Nodale C, Sheffer M, Jacob-Hirsch J, Folgiero V, Falcioni R, Aiello A, Garufi A, Rechavi G, Givol D, D'Orazi G. HIPK2 downregulates vimentin and inhibits breast cancer cell invasion. Cancer Biol Ther 13: 198– 205. Pierantoni GM, Fedele M, Pentimalli F, Benvenuto G, Pero R, Viglietto G, Santoro M, Chiariotti L, Fusco A.
High mobility group I (Y) proteins bind HIPK2, a serine-threonine kinase protein which inhibits cell growth. Oncogene 20: 6132– 6141. Poon CL, Zhang X, Lin JI, Manning SA, Harvey KF. Homeodomain-interacting protein kinase regulates hippo pathway-dependent tissue growth. Curr Biol 22: 1587– 1594. Praitis V, Casey E, Collar D, Austin J.
Creation of low-copy integrated transgenic lines in Caenorhabditis elegans. Genetics 157: 1217– 1226. Raich WB, Moorman C, Lacefield CO, Lehrer J, Bartsch D, Plasterk RH, Kandel ER, Hobert O. Characterization of Caenorhabditis elegans homologs of the Down syndrome candidate gene DYRK1A. Genetics 163: 571– 580.
Rinaldo C, Prodosmo A, Siepi F, Soddu S. HIPK2: a multitalented partner for transcription factors in DNA damage response and development. Biochem Cell Biol 85: 411– 418.
Rinaldo C, Siepi F, Prodosmo A, Soddu S. HIPKs: Jack of all trades in basic nuclear activities. Biochim Biophys Acta 1783: 2124– 2129. Samuelson AV, Carr CE, Ruvkun G. Gene activities that mediate increased life span of C. Elegans insulin-like signaling mutants. Genes Dev 21: 2976– 2994.
Sijen T, Fleenor J, Simmer F, Thijssen KL, Parrish S, Timmons L, Plasterk RH, Fire A. On the role of RNA amplification in dsRNA-triggered gene silencing. Cell 107: 465– 476. Tijsterman M, Okihara KL, Thijssen K, Plasterk RH.
PPW-1, a PAZ/PIWI protein required for efficient germline RNAi, is defective in a natural isolate of C. Curr Biol 12: 1535– 1540. Trapasso F, Aqeilan RI, Iuliano R, Visone R, Gaudio E, Ciuffini L, Alder H, Paduano F, Pierantoni GM, Soddu S, Croce CM, Fusco A.
Targeted disruption of the murine homeodomain-interacting protein kinase-2 causes growth deficiency in vivo and cell cycle arrest in vitro. DNA Cell Biol 28: 161– 167. Tursun B, Cochella L, Carrera I, Hobert O. A toolkit and robust pipeline for the generation of fosmid-based reporter genes in C. PLoS One 4: e4625.
Verheyen EM, Swarup S, Lee W. Hipk proteins dually regulate Wnt/Wingless signal transduction. Fly (Austin) 6: 126– 131.
Waters K, Yang AZ, Reinke V. Genome-wide analysis of germ cell proliferation in C.
Elegans identifies VRK-1 as a key regulator of CEP-1/p53. Dev Biol 344: 1011– 1025. Waters KA, Reinke V.
Extrinsic and intrinsic control of germ cell proliferation in Caenorhabditis elegans. Mol Reprod Dev 78: 151– 160. Wei G, Ku S, Ma GK, Saito S, Tang AA, Zhang J, Mao JH, Appella E, Balmain A, Huang EJ. HIPK2 represses beta-catenin-mediated transcription, epidermal stem cell expansion, and skin tumorigenesis. Proc Natl Acad Sci USA 104: 13040– 13045.
1/50 Infantry Vietnam
Winter M, Sombroek D, Dauth I, Moehlenbrink J, Scheuermann K, Crone J, Hofmann TG. Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR. Nat Cell Biol 10: 812– 824. Zhang J, Pho V, Bonasera SJ, Holtzman J, Tang AT, Hellmuth J, Tang S, Janak PH, Tecott LH, Huang EJ.
Reader Safety Glasses 1.50 Full Lens
Essential function of HIPK2 in TGFbeta-dependent survival of midbrain dopamine neurons. Nat Neurosci 10: 77– 86. Zhang Y, Nash L, Fisher AL. A simplified, robust, and streamlined procedure for the production of C. Elegans transgenes via recombineering. BMC Dev Biol 8: 119.
Related content.