Platelet-activating factor acetylhydrolase 1B3 (PAFAH1B3) is required for the formation of the meiotic spindle during in vitro oocyte maturation
L. T. M. Vandenberghe A F , B. Heindryckx B , K. Smits A , K. Szymanska C , N. Ortiz-Escribano A , M. Ferrer-Buitrago B , K. Pavani A , L. Peelman D , D. Deforce E , P. De Sutter B , A. Van Soom A and C. De Schauwer AA Department of Reproduction, Obstetrics and Herd Health, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium.
B Ghent-Fertility and Stem Cell Team (G-FaST), Department for Reproductive Medicine, Ghent University Hospital, 9000 Ghent, Belgium.
C Physiology Group, Department of Basic Medical Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
D Department of Nutrition, Genetics and Ethology, Faculty of Veterinary Medicine, Ghent University, Heidestraat 19, 9820 Merelbeke, Belgium.
E Laboratory of Pharmaceutical Biotechnology, Ghent University, Harelbekestraat 72, 9000 Ghent, Belgium.
F Corresponding author. Email: lynnt.vandenberghe@ugent.be
Reproduction, Fertility and Development 30(12) 1739-1750 https://doi.org/10.1071/RD18019
Submitted: 13 January 2018 Accepted: 6 June 2018 Published: 16 July 2018
Abstract
Platelet-activating factor (PAF) is a well-described autocrine growth factor involved in several reproductive processes and is tightly regulated by its hydrolysing enzyme, PAF acetylhydrolase 1B (PAFAH1B). This intracellular enzyme consists of three subunits: one regulatory, 1B1, and two catalytic, 1B2 and 1B3. PAFAH1B3 has remained uncharacterised until now. Here, we report that PAFAH1B3 is present during the different stages of the first meiotic division in bovine, murine and human oocytes. In these species, the PAFAH1B3 subunit was clearly present in the germinal vesicle, while at metaphase I and II, it localised primarily at the meiotic spindle structure. In cattle, manipulation of the microtubules of the spindle by nocodazole, taxol or cryopreservation revealed a close association with PAFAH1B3. On the other hand, disruption of the enzyme activity either by P11, a selective inhibitor of PAFAH1B3, or by PAFAH1B3 antibody microinjection, caused arrest at the MI stage with defective spindle morphology and consequent failure of first polar body extrusion. In conclusion, our results show that one of the catalytic subunits of PAFAH1B, namely PAFAH1B3, is present in bovine, murine and human oocytes and that it plays a functional role in spindle formation and meiotic progression during bovine oocyte maturation.
Additional keywords: alpha-tubulin, assisted reproduction, maturation failure, meiosis, platelet-activating factor.
References
Albarracin, J. L., Morato, R., Rojas, C., and Mogas, T. (2005). Effects of vitrification in open pulled straws on the cytology of in vitro matured prepubertal and adult bovine oocytes. Theriogenology 63, 890–901.| Effects of vitrification in open pulled straws on the cytology of in vitro matured prepubertal and adult bovine oocytes.Crossref | GoogleScholarGoogle Scholar |
Alonso, A., D’Silva, S., Rahman, M., Meluh, P. B., Keeling, J., Meednu, N., Hoops, H. J., and Miller, R. K. (2012). The yeast homologue of the microtubule-associated protein Lis1 interacts with the sumoylation machinery and a SUMO-targeted ubiquitin ligase. Mol. Biol. Cell 23, 4552–4566.
| The yeast homologue of the microtubule-associated protein Lis1 interacts with the sumoylation machinery and a SUMO-targeted ubiquitin ligase.Crossref | GoogleScholarGoogle Scholar |
Amiel, M.-L., Testart, J., and Benveniste, J. (1991). Platelet-activating factor-acether is a component of human follicular fluid. Fertil. Steril. 56, 62–65.
| Platelet-activating factor-acether is a component of human follicular fluid.Crossref | GoogleScholarGoogle Scholar |
Assadi, A. H., Zhang, G., Beffert, U., McNeil, R. S., Renfro, A. L., Niu, S., Quattrocchi, C. C., Antalffy, B. A., Sheldon, M., Armstrong, D. D., Wynshaw-Boris, A., Herz, J., D’Arcangelo, G., and Clark, G. D. (2003). Interaction of reelin signaling and Lis1 in brain development. Nat. Genet. 35, 270–276.
| Interaction of reelin signaling and Lis1 in brain development.Crossref | GoogleScholarGoogle Scholar |
Bałakier, H., and Tarkowski, A. K. (1980). The role of germinal vesicle karyoplasm in the development of male pronucleus in the mouse. Exp. Cell Res. 128, 79–85.
| The role of germinal vesicle karyoplasm in the development of male pronucleus in the mouse.Crossref | GoogleScholarGoogle Scholar |
Battaglia, D. E., Goodwin, P., Klein, N. A., and Soules, M. R. (1996). Fertilization and early embryology: influence of maternal age on meiotic spindle assembly oocytes from naturally cycling women. Hum. Reprod. 11, 2217–2222.
| Fertilization and early embryology: influence of maternal age on meiotic spindle assembly oocytes from naturally cycling women.Crossref | GoogleScholarGoogle Scholar |
Beall, S., Brenner, C., and Segars, J. (2010). Oocyte maturation failure: a syndrome of bad eggs. Fertil. Steril. 94, 2507–2513.
| Oocyte maturation failure: a syndrome of bad eggs.Crossref | GoogleScholarGoogle Scholar |
Brunet, S., and Maro, B. (2005). Cytoskeleton and cell cycle control during meiotic maturation of the mouse oocyte: integrating time and space. Reproduction 130, 801–811.
| Cytoskeleton and cell cycle control during meiotic maturation of the mouse oocyte: integrating time and space.Crossref | GoogleScholarGoogle Scholar |
Chang, J. W., Zuhl, A. M., Speers, A. E., Niessen, S., Brown, S. J., Mulvihill, M. M., Fan, Y. C., Spicer, T. P., Southern, M., and Scampavia, L. (2015). Selective inhibitor of platelet-activating factor acetylhydrolases 1b2 and 1b3 that impairs cancer cell survival. ACS Chem. Biol. 10, 925–932.
| Selective inhibitor of platelet-activating factor acetylhydrolases 1b2 and 1b3 that impairs cancer cell survival.Crossref | GoogleScholarGoogle Scholar |
Chen, J., Yang, L. L., Foulks, J. M., Weyrich, A. S., Marathe, G. K., and McIntyre, T. M. (2007). Intracellular PAF catabolism by PAF acetylhydrolase counteracts continual PAF synthesis. J. Lipid Res. 48, 2365–2376.
| Intracellular PAF catabolism by PAF acetylhydrolase counteracts continual PAF synthesis.Crossref | GoogleScholarGoogle Scholar |
Collin, P., Nashchekina, O., Walker, R., and Pines, J. (2013). The spindle assembly checkpoint works like a rheostat rather than a toggle switch. Nat. Cell Biol. 15, 1378–1385.
| The spindle assembly checkpoint works like a rheostat rather than a toggle switch.Crossref | GoogleScholarGoogle Scholar |
Combelles, C. M., Albertini, D. F., and Racowsky, C. (2003). Distinct microtubule and chromatin characteristics of human oocytes after failed in vivo and in vitro meiotic maturation. Hum. Reprod. 18, 2124–2130.
| Distinct microtubule and chromatin characteristics of human oocytes after failed in vivo and in vitro meiotic maturation.Crossref | GoogleScholarGoogle Scholar |
Danylevska, A., Kovacovicova, K., Awadova, T., and Anger, M. (2014). The frequency of precocious segregation of sister chromatids in mouse female meiosis I is affected by genetic background. Chromosome Res. 22, 365–373.
| The frequency of precocious segregation of sister chromatids in mouse female meiosis I is affected by genetic background.Crossref | GoogleScholarGoogle Scholar |
Destouni, A., Esteki, M. Z., Catteeuw, M., Tšuiko, O., Dimitriadou, E., Smits, K., Kurg, A., Salumets, A., Van Soom, A., and Voet, T. (2016). Zygotes segregate entire parental genomes in distinct blastomere lineages causing cleavage-stage chimerism and mixoploidy. Genome Res. 26, 567–578.
| Zygotes segregate entire parental genomes in distinct blastomere lineages causing cleavage-stage chimerism and mixoploidy.Crossref | GoogleScholarGoogle Scholar |
Ding, C., Liang, X., Ma, L., Yuan, X., and Zhu, X. (2009). Opposing effects of Ndel1 and α1 or α2 on cytoplasmic dynein through competitive binding to Lis1. J. Cell Sci. 122, 2820–2827.
| Opposing effects of Ndel1 and α1 or α2 on cytoplasmic dynein through competitive binding to Lis1.Crossref | GoogleScholarGoogle Scholar |
Ebner, T., Moser, M., Shebl, O., Sommerguber, M., and Tews, G. (2008). Prognosis of oocytes showing aggregation of smooth endoplasmic reticulum. Reprod. Biomed. Online 16, 113–118.
| Prognosis of oocytes showing aggregation of smooth endoplasmic reticulum.Crossref | GoogleScholarGoogle Scholar |
Edwards, R. G. (1965). Maturation in vitro of mouse, sheep, cow, pig, rhesus monkey and human ovarian oocytes. Nature 208, 349–351.
| Maturation in vitro of mouse, sheep, cow, pig, rhesus monkey and human ovarian oocytes.Crossref | GoogleScholarGoogle Scholar |
Fagerberg, L., Hallström, B. M., Oksvold, P., Kampf, C., Djureinovic, D., Odeberg, J., Habuka, M., Tahmasebpoor, S., Danielsson, A., Edlund, K., Asplund, A., Sjöstedt, E., Lundberg, E., Szigyarto, C. A.-K., Skogs, M., Takanen, J. O., Berling, H., Tegel, H., Mulder, J., Nilsson, P., Schwenk, J. M., Lindskog, C., Danielsson, F., Mardinoglu, A., Sivertsson, Å., von Feilitzen, K., Forsberg, M., Zwahlen, M., Olsson, I., Navani, S., Huss, M., Nielsen, J., Ponten, F., and Uhlén, M. (2014). Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol. Cell. Proteomics 13, 397–406.
| Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics.Crossref | GoogleScholarGoogle Scholar |
Faulkner, N. E., Dujardin, D. L., Tai, C. Y., Vaughan, K. T., O’Connell, C. B., Wang, Y., and Vallee, R. B. (2000). A role for the lissencephaly gene LIS1 in mitosis and cytoplasmic dynein function. Nat. Cell Biol. 2, 784–791.
| A role for the lissencephaly gene LIS1 in mitosis and cytoplasmic dynein function.Crossref | GoogleScholarGoogle Scholar |
Goossens, K., Van Poucke, M., Van Soom, A., Vandesompele, J., Van Zeveren, A., and Peelman, L. J. (2005). Selection of reference genes for quantitative real-time PCR in bovine preimplantation embryos. BMC Dev. Biol. 5, 27.
| Selection of reference genes for quantitative real-time PCR in bovine preimplantation embryos.Crossref | GoogleScholarGoogle Scholar |
Gorbsky, G. J. (2001). The mitotic spindle checkpoint. Curr. Biol. 11, R1001–R1004.
| The mitotic spindle checkpoint.Crossref | GoogleScholarGoogle Scholar |
Grealy, M., Diskin, M. G., and Sreenan, J. M. (1996). Protein content of cattle oocytes and embryos from the two-cell to the elongated blastocyst stage at Day 16. J. Reprod. Fertil. 107, 229–233.
| Protein content of cattle oocytes and embryos from the two-cell to the elongated blastocyst stage at Day 16.Crossref | GoogleScholarGoogle Scholar |
Harrison, K. L., Sherrin, D. A., and Keeping, J. D. (2000). Repeated oocyte maturation block. J. Assist. Reprod. Genet. 17, 231–233.
| Repeated oocyte maturation block.Crossref | GoogleScholarGoogle Scholar |
Hassold, T., and Hunt, P. (2001). To err (meiotically) is human: the genesis of human aneuploidy. Nat. Rev. Genet. 2, 280–291.
| To err (meiotically) is human: the genesis of human aneuploidy.Crossref | GoogleScholarGoogle Scholar |
Hattori, M., Adachi, H., Tsujimoto, M., Arai, H., and Inoue, K. (1994). The catalytic subunit of bovine brain platelet-activating factor acetylhydrolase is a novel type of serine esterase. J. Biol. Chem. 269, 23150–23155.
Heindryckx, B., De Sutter, P., Gerris, J., Dhont, M., and Van der Elst, J. (2007). Embryo development after successful somatic cell nuclear transfer to in vitro matured human germinal vesicle oocytes. Hum. Reprod. 22, 1982–1990.
| Embryo development after successful somatic cell nuclear transfer to in vitro matured human germinal vesicle oocytes.Crossref | GoogleScholarGoogle Scholar |
Heindryckx, B., Lierman, S., Combelles, C., Cuvelier, C., Gerris, J., and De Sutter, P. (2011). Aberrant spindle structures responsible for recurrent human metaphase I oocyte arrest with attempts to induce meiosis artificially. Hum. Reprod. 26, 791–800.
| Aberrant spindle structures responsible for recurrent human metaphase I oocyte arrest with attempts to induce meiosis artificially.Crossref | GoogleScholarGoogle Scholar |
Heras, S., De Coninck, D. I., Van Poucke, M., Goossens, K., Pascottini, O. B., Van Nieuwerburgh, F., Deforce, D., De Sutter, P., Leroy, J. L., and Gutierrez-Adan, A. (2016). Suboptimal culture conditions induce more deviations in gene expression in male than female bovine blastocysts. BMC Genomics 17, 72.
| Suboptimal culture conditions induce more deviations in gene expression in male than female bovine blastocysts.Crossref | GoogleScholarGoogle Scholar |
Hirotsune, S., Fleck, M. W., Gambello, M. J., Bix, G. J., Chen, A., Clark, G. D., Ledbetter, D. H., McBain, C. J., and Wynshaw-Boris, A. (1998). Graded reduction of Pafah1b1 (Lis1) activity results in neuronal migration defects and early embryonic lethality. Nat. Genet. 19, 333–339.
| Graded reduction of Pafah1b1 (Lis1) activity results in neuronal migration defects and early embryonic lethality.Crossref | GoogleScholarGoogle Scholar |
Holubcová, Z., Blayney, M., Elder, K., and Schuh, M. (2015). Error-prone chromosome-mediated spindle assembly favors chromosome segregation defects in human oocytes. Science 348, 1143–1147.
| Error-prone chromosome-mediated spindle assembly favors chromosome segregation defects in human oocytes.Crossref | GoogleScholarGoogle Scholar |
Jeon, H.-J., You, S. Y., Park, Y. S., Chang, J. W., Kim, J.-S., and Oh, J. S. (2016). TCTP regulates spindle microtubule dynamics by stabilizing polar microtubules during mouse oocyte meiosis. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1863, 630–637.
Kiermer, V. (2008). Antibodypedia. Nat. Methods 5, 860–860.
| Antibodypedia.Crossref | GoogleScholarGoogle Scholar |
Koizumi, H., Yamaguchi, N., Hattori, M., Ishikawa, T.-o., Aoki, J., Taketo, M. M., Inoue, K., and Arai, H. (2003). Targeted disruption of intracellular Type I platelet activating factor-acetylhydrolase catalytic subunits causes severe impairment in spermatogenesis. J. Biol. Chem. 278, 12489–12494.
| Targeted disruption of intracellular Type I platelet activating factor-acetylhydrolase catalytic subunits causes severe impairment in spermatogenesis.Crossref | GoogleScholarGoogle Scholar |
Kuliev, A., Cieslak, J., Ilkevitch, Y., and Verlinsky, Y. (2003). Chromosomal abnormalities in a series of 6733 human oocytes in preimplantation diagnosis for age-related aneuploidies. Reprod. Biomed. Online 6, 54–59.
| Chromosomal abnormalities in a series of 6733 human oocytes in preimplantation diagnosis for age-related aneuploidies.Crossref | GoogleScholarGoogle Scholar |
Levran, D., Farhi, J., Nahum, H., Glezerman, M., and Weissman, A. (2002). Maturation arrest of human oocytes as a cause of infertility: case report. Hum. Reprod. 17, 1604–1609.
| Maturation arrest of human oocytes as a cause of infertility: case report.Crossref | GoogleScholarGoogle Scholar |
Li, W., Goossens, K., Van Poucke, M., Forier, K., Braeckmans, K., Van Soom, A., and Peelman, L. J. (2016). High oxygen tension increases global methylation in bovine 4-cell embryos and blastocysts but does not affect general retrotransposon expression. Reprod. Fertil. Dev. 28, 948–959.
| High oxygen tension increases global methylation in bovine 4-cell embryos and blastocysts but does not affect general retrotransposon expression.Crossref | GoogleScholarGoogle Scholar |
Liu, L., and Keefe, D. L. (2008). Defective cohesin is associated with age-dependent misaligned chromosomes in oocytes. Reprod. Biomed. Online 16, 103–112.
| Defective cohesin is associated with age-dependent misaligned chromosomes in oocytes.Crossref | GoogleScholarGoogle Scholar |
Longo, F. J., and Chen, D.-Y. (1985). Development of cortical polarity in mouse eggs: involvement of the meiotic apparatus. Dev. Biol. 107, 382–394.
| Development of cortical polarity in mouse eggs: involvement of the meiotic apparatus.Crossref | GoogleScholarGoogle Scholar |
Menasha, J., Levy, B., Hirschhorn, K., and Kardon, N. B. (2005). Incidence and spectrum of chromosome abnormalities in spontaneous abortions: new insights from a 12-year study. Genet. Med. 7, 251–263.
| Incidence and spectrum of chromosome abnormalities in spontaneous abortions: new insights from a 12-year study.Crossref | GoogleScholarGoogle Scholar |
Mrazek, M., and Fulka, J. (2003). Failure of oocyte maturation: possible mechanisms for oocyte maturation arrest. Hum. Reprod. 18, 2249–2252.
| Failure of oocyte maturation: possible mechanisms for oocyte maturation arrest.Crossref | GoogleScholarGoogle Scholar |
Narahara, H., Tanaka, Y., Kawano, Y., Miyakawa, I., and Johnston, J. M. (1996) Platelet-activating factor acetylhydrolase activity in human follicular fluid. In ‘Platelet-Activating Factor and Related Lipid Mediators 2’. (Eds S. Nigam, G. Kunkel, S. M. Prescott) pp. 121–127. (Springer Science+Business Media: New York.)
Ortiz-Escribano, N., Smits, K., Piepers, S., Van den Abbeel, E., Woelders, H., and Van Soom, A. (2016). Role of cumulus cells during vitrification and fertilization of mature bovine oocytes: effects on survival, fertilization, and blastocyst development. Theriogenology 86, 635–641.
| Role of cumulus cells during vitrification and fertilization of mature bovine oocytes: effects on survival, fertilization, and blastocyst development.Crossref | GoogleScholarGoogle Scholar |
Paradis, F., Vigneault, C., Robert, C., and Sirard, M. A. (2005). RNA interference as a tool to study gene function in bovine oocytes. Mol. Reprod. Dev. 70, 111–121.
| RNA interference as a tool to study gene function in bovine oocytes.Crossref | GoogleScholarGoogle Scholar |
Payne, C., St John, J. C., Ramalho‐Santos, J., and Schatten, G. (2003). LIS1 association with dynactin is required for nuclear motility and genomic union in the fertilized mammalian oocyte. Cell Motil. Cytoskeleton 56, 245–251.
| LIS1 association with dynactin is required for nuclear motility and genomic union in the fertilized mammalian oocyte.Crossref | GoogleScholarGoogle Scholar |
Shin, H., Kwon, S., Song, H., and Lim, H. J. (2014). The transcription factor Egr3 is a putative component of the microtubule organizing center in mouse oocytes. PLoS One 9, e94708.
| The transcription factor Egr3 is a putative component of the microtubule organizing center in mouse oocytes.Crossref | GoogleScholarGoogle Scholar |
Sirard, M. A. (2001). Resumption of meiosis: mechanism involved in meiotic progression and its relation with developmental competence. Theriogenology 55, 1241–1254.
| Resumption of meiosis: mechanism involved in meiotic progression and its relation with developmental competence.Crossref | GoogleScholarGoogle Scholar |
Smith, D. S., Niethammer, M., Ayala, R., Zhou, Y., Gambello, M. J., Wynshaw-Boris, A., and Tsai, L.-H. (2000). Regulation of cytoplasmic dynein behaviour and microtubule organization by mammalian Lis1. Nat. Cell Biol. 2, 767–775.
| Regulation of cytoplasmic dynein behaviour and microtubule organization by mammalian Lis1.Crossref | GoogleScholarGoogle Scholar |
Tanghe, S., Van Soom, A., Nauwynck, H., Coryn, M., and de Kruif, A. (2002). Minireview: functions of the cumulus oophorus during oocyte maturation, ovulation, and fertilization. Mol. Reprod. Dev. 61, 414–424.
| Minireview: functions of the cumulus oophorus during oocyte maturation, ovulation, and fertilization.Crossref | GoogleScholarGoogle Scholar |
Uhlen, M., Bandrowski, A., Carr, S., Edwards, A., Ellenberg, J., Lundberg, E., Rimm, D. L., Rodriguez, H., Hiltke, T., and Snyder, M. (2016). A proposal for validation of antibodies. Nat. Methods 13, 823–827.
| A proposal for validation of antibodies.Crossref | GoogleScholarGoogle Scholar |
Verlhac, M.-H., de Pennart, H., Maro, B., Cobb, M. H., and Clarke, H. J. (1993). MAP kinase becomes stably activated at metaphase and is associated with microtubule-organizing centers during meiotic maturation of mouse oocytes. Dev. Biol. 158, 330–340.
| MAP kinase becomes stably activated at metaphase and is associated with microtubule-organizing centers during meiotic maturation of mouse oocytes.Crossref | GoogleScholarGoogle Scholar |
Wang, H. H., Cui, Q., Zhang, T., Wang, Z., Ouyang, Y., Shen, W., Ma, J., Schatten, H., and Sun, Q. (2016). Rab3A, Rab27A, and Rab35 regulate different events during mouse oocyte meiotic maturation and activation. Histochem. Cell Biol. 145, 647–657.
| Rab3A, Rab27A, and Rab35 regulate different events during mouse oocyte meiotic maturation and activation.Crossref | GoogleScholarGoogle Scholar |
Windt, M.-L., Coetzee, K., Kruger, T., Marino, H., Kitshoff, M., and Sousa, M. (2001). Ultrastructural evaluation of recurrent and in vitro maturation resistant metaphase I arrested oocytes. Case report. Hum. Reprod. 16, 2394–2398.
| Ultrastructural evaluation of recurrent and in vitro maturation resistant metaphase I arrested oocytes. Case report.Crossref | GoogleScholarGoogle Scholar |
Yao, G.-D., Shi, S.-L., Song, W.-Y., Jin, H.-X., Peng, Z.-F., Yang, H.-Y., Wang, E.-Y., and Sun, Y.-P. (2015). Role of PAFAH1B1 in human spermatogenesis, fertilization and early embryonic development. Reprod. Biomed. Online 31, 613–624.
| Role of PAFAH1B1 in human spermatogenesis, fertilization and early embryonic development.Crossref | GoogleScholarGoogle Scholar |
Zhang, G., Assadi, A. H., McNeil, R. S., Beffert, U., Wynshaw-Boris, A., Herz, J., Clark, G. D., and D’Arcangelo, G. (2007). The Pafah1b complex interacts with the reelin receptor VLDLR. PLoS One 2, e252.
| The Pafah1b complex interacts with the reelin receptor VLDLR.Crossref | GoogleScholarGoogle Scholar |
Zhang, Y., Duan, X., Cao, R., Liu, H.-L., Cui, X.-S., Kim, N.-H., Rui, R., and Sun, S.-C. (2014). Small GTPase RhoA regulates cytoskeleton dynamics during porcine oocyte maturation and early embryo development. Cell Cycle 13, 3390–3403.
| Small GTPase RhoA regulates cytoskeleton dynamics during porcine oocyte maturation and early embryo development.Crossref | GoogleScholarGoogle Scholar |
Zimdahl, B., Ito, T., Blevins, A., Bajaj, J., Konuma, T., Weeks, J., Koechlein, C. S., Kwon, H. Y., Arami, O., and Rizzieri, D. (2014). Lis1 regulates asymmetric division in hematopoietic stem cells and in leukemia. Nat. Genet. 46, 245–252.
| Lis1 regulates asymmetric division in hematopoietic stem cells and in leukemia.Crossref | GoogleScholarGoogle Scholar |