Changing genetic world of IVF, stem cells and PGD. B. Polarities and gene expression in differentiating embryo cells and stem cells

Reproductive BioMedicine Online

Volumn 11, Issue 6, 2005, Pages 761-776

  Edwards, R G ^a  

^a Dry Drayton   (United Kingdom)

Author keywords

Embryonic gene analysis; Haemopoietic and mesenchymal stem cells; Human and mouse preimplantation embryos; Inner cell mass; Polarities; Spindle rotation; Trophectoderm

Indexed keywords

COMPLEMENTARY DNA; TRANSCRIPTOME;

ANALYTIC METHOD; BLASTOMERE; CELL DIFFERENTIATION; CELL DIVISION; CELL FUNCTION; DNA LIBRARY; DNA MICROARRAY; EMBRYO DEVELOPMENT; EMBRYO GROWTH; EMBRYONIC STEM CELL; FERTILIZATION IN VITRO; FLUORESCENCE IN SITU HYBRIDIZATION; GENE EXPRESSION; GENETIC ANALYSIS; HETEROPLOIDY; HUMAN; INNER CELL MASS; NIDATION; NONHUMAN; OOCYTE; POLYMERASE CHAIN REACTION; PRENATAL DIAGNOSIS; REVIEW; RNA INTERFERENCE;

EID: 29444436682     PISSN: 14726483     EISSN: None     Source Type: Journal    
DOI: 10.1016/S1472-6483(10)61696-3     Document Type: Review

References (129)

1. Adjaye J, Bolton V, Monk M 1999 Developmental expression of specific genes detected in high-quality cDNA libraries from single human preimplantation embryos. Gene 237, 373-383.
2. Antczak M, van Blerkom J 1999 Temporal and spatial aspects of fragmentation in early embryos: possible effects on developmental competence and association with the differential of regulatory proteins from polarized domains. Human Reproduction 14, 429-447.
3. Antczak M, van Blerkom J 1997 Oocyte influences on early development: leptin and STAT3 are polarised in mouse and human oocytes and differentially distributed within the cell of the preimplantation embryo. Molecular Human Reproduction 3, 1067-1086.
4. Bao Z, Murray J, Waterston RH 2004 Automated cell lineaging and single-cell gene expression profiling in C. elegans. Identification of functional elements in mammalian genomes. Cold Spring Harbor Symposium, New York.
5. Bermudez MG, Wells D, Malter H et al. 2004 Expression profiles of individual human oocytes using microarray technology. Reproductive BioMedicine Online 8, 325-337.
6. Bernstein E, Kim SY, Carmell MA et al. 2003 Dicer is essential for mouse development. Nature Genetics 35, 215-217.
7. Braude P, Bolton V, Moore S 1988 Human gene expression first occurs between the the four- and eight-cell stages of preimplantation development. Nature 332, 459-461.
8. Cáceres L, Nilson LA 2005 Production of gurken in the nurse cells is sufficient for axis determination in the Drosophila oocyte. Development 132, 2345-2353.
9. Cameo P, Bischof P, Calvo JC 2003 Effect of leptin on progesterone, human chorionic gonadotropin, and interleukin-6 secretion by human term trophoblast cells in culture. Biology of Reproduction 68, 472-477
10. Castellucci M, De Matteis R, Meisser A et al. 2000 Leptin modulates extracellular matrix molecules and metalloproteinases: possible implications for trophoblast invasion. Molecular Human Reproduction 6, 951-958.
11. Cauffman G, Van de Velde H, Liebaers I et al. 2005 Oct-4 mRNA and protein expression during human preimplantation development. Molecular Human Reproduction 11, 173-181.
12. Cervero A, Horcajadas JA, Doinguez F et al. 2005 Leptin system in embryo development and implantation: a protein in search of a function. Reproductive BioMedicine Online 10, 217-223.
13. Chambers I, Colby D, Robertson M 2003 Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113, 643-655.
14. Chardonnens D, Cameo P, Aubert ML et al. 1999 Modulation of human cytotrophoblastic leptin secretion by interleukin-1 alpha and 17beta-oestradiol and its effect on HCG secretion. Molecular Human Reproduction 5, 1077-1082.
15. Chen C-Z, Li L, Lodish HF, Bartel DP 2004 MicroRNAs modulate haemopoietic lineage differentiation. Science 303, 83.
16. Chian R-C 2004 In vitro maturation of immature oocytes for infertile women with PCOS. Reproductive BioMedicine Online 8, 547-552.
17. Dalcq AM 1957 Introduction to General Embryology. Oxford University Press, London.
18. Dalcq AM 1951 New descriptive and experimental data concerning the mammalian egg, principally of the rat. Kon. Nederland Ak. Wetens. Proceedings of the Section of Science 54, 351.
19. Dean W, Bowden L, Aitchison A et al. 1998 Altered imprinted gene methylation and expression in completely ES cell-derived mouse fetuses: association with aberrant phenotypes. Development 125, 2273-2282.
20. Edwards RG 2005 Genetics of polarity in mammalian embryos. Reproductive BioMedicine Online 11, 104-114.
21. Edwards RG 2002 Aspects of the molecular regulation of early mammalian development. Reproductive BioMedicine Online 6, 97-113.
22. Edwards RG 2001 Molecular and morphogenetic homologies between oocytes and embryos in Drosophila, C. elegans, Xenopus and mammals. Reproductive BioMedicine Online 3, 138-160.
23. Edwards RG, Beard HK 1999 Hypothesis: sex determination and germline formation are committed at the pronucleate stage in mammalian embryos. Molecular Human Reproduction 5, 595-606.
24. Edwards RG, Beard HK 1997 Oocyte polarity and cell determination in early mammalian embryos. Molecular Human Reproduction 3, 863-905.
25. Edwards RG, Hansis C 2005 Initial differentiation of blastomeres in 4-cell embryos and its significance for early embryogenesis and implantation. Reproductive BioMedicine Online 11, 206-218.
26. Edwards RG, Sirlin JL 1956 Studies on gametogenesis, fertilization and early development in the mouse using radioactive tracers. Proceedings of the Second World Congress on Fertility and Sterility, Naples, pp. 376-386.
27. Enver T, Graves M 1998 Loops, lineage and leukemia. Cell 94, 9-12.
28. Etienne-Mannerville S 2004 Cdc42 - the centre of polarity. Journal of Cell Science, 117, 1291-1300.
29. Fire A, Xu S, Lontgomery MK et al. 1998 Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806-811.
30. Fujimori T, Kurotaki Y, Miyazaki J, Nabeshima Y 2003 Analysis of cell lineage in two- and four-cell mouse embryos. Development 130, 5113-5122.
31. Fuzzi B, Rizzo R, Criscuoli L et al. 2002 HLA-G expression in early embryos is a fundamental prerequisite for the obtainment of pregnancy. European Journal of Immunology 32, 311-315.
32. Gardner RL 2006 Weaknesses in the case against pre-patterning in the mouse. Reproductive BioMedicine Online 12, in press.
33. Gardner RL 2001 Specification of embryonic axes begins before cleavage in normal mouse development. Development 128, 839-847.
34. Gardner RL, Davies TJ 2003 Is the plane of the first cleavage related to the point of sperm entry in the mouse? Reproductive BioMedicine Online 6, 157-160.
35. Gonzales RR, Caballero-Campo P, Jasper M et al. 2002 Leptin and leptin receptor are expressed in human endometrium and endometrial leptin secretion is regulated by the human blastocyst. Journal of Clinical Endocrinology and Metabolism 85, 4885-4888.
36. Goto T, Adjaye J, Rodeck CH et al. 1999 Identification of genes expressed in human primordial germ cells at the time of entry of the female germ line into meiosis. Molecular Human Reproduction 5, 851-860.
37. Graham CF, Duesson ZA 1978 Features of cell lineage in preimplantation mouse development. Journal of Embryology and Experimental Morphology 48, 53-72.
38. Green E, Miller W, Zhang M (Arrangers) 2004 Identification of Functional Elements in Mammalian Germline. Genomics workshop. Cold Spring Harbor Laboratory, New York
39. Grishok A, Pasquinelle AE, Conte D et al. 2001 Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C. elegans developmental timing. Cell 106, 23-34.
40. Grünert S, St Johnston D 1996 RNA localization and the development of asymmetry during Drosophila oogenesis. Current Opinion in Genetics and Development 6, 395-402.
41. Gulyas BJ 1975 A re-examination of cleavage patterns in eutherian mammalian eggs: rotation of blastomere pairs during second cleavage of the rabbit. Journal of Experimental Zoology 193, 235-248.
42. Gunsalus KC, Ge H, Schetter AJ et al. 2005 Predictive models of molecular machines involved in Caenorhabditis elegans early embryogenesis. Nature 436, 861-865.
43. Guo S, Kemphues KJ 1996 Molecular genetics of asymmetric cleavage in the early Caenorhabditis elegans embryo. Current Opinion in Genetics and Development 6, 408-415.
44. Haffner-Krausz R, Gorivodsky M, Chen Y et al. 1999 Expression of F gfr2 in the early mouse embryo indicates its involvement in preimplantation development. Mechanisms of Development 85, 167-172.
45. Hamatani T, Carter MG, Sharov AA, Ko MSH 2004 Dynamics of global gene expression changes during mouse preimplantation development. Developmental Cell 6, 117-131.
46. Handyside AH, Johnson MH 1978 Temporal and spatial patterns of the synthesis of tissue-specific polypeptides in the preimplantation mouse embryo. Journal of Embryology and Experimental Morphology 44, 191-199.
47. Hansis C, Edwards RG 2003 Cell differentiation in the preimplantation human embryo. Reproductive BioMedicine Online 6, 215-220.
48. Hansis C, Grifo JA, Krey LC 2004 Candidate lineage marker genes in human preimplantation embryos. Reproductive BioMedicine Online 8, 577-583.
49. Hansis C, Grifo J, Tang YX, Krey L 2002 Assessment of β-HCG, β-LH mRNA and ploidy individual blastomeres. Reproductive BioMedicine Online 5, 156-161.
50. Hansis C, Tang YX, Grifo JA, Krey LC 2001 Analysis of oct-4 expression and ploidy in individual human blastomeres. Molecular Human Reproduction 7, 155-161.
51. Hansis C, Grifo JA, Krey LC 2000 Oct-4 expression in inner cell mass and trophectoderm of human blastocysts. Molecular Human Reproduction 6, 999-1004.
52. Hatfield SD, Shcherbata HR, Fischer KA et al. 2005 Stem cell division is regulated by the microRNA pathway. Nature 435, 974-978.
53. Hattori N, Nishino K, Ko YG et al. 2004 Epigenetic control of mouse Oct-4 gene expression in embryonic stem cells and trophoblast stem cells. Journal of Biological Chemistry 279, 17063-17069.
54. Hiiragi T, Solter D 2004 First cleavage plane of the mouse egg is not predetermined but defined by the topology of the two apposing pronuclei. Nature 430, 360-364.
55. Hosler BA, LaRosa GJ, Grippo JF et al. 1989 Expression of REX-1, a gene containing zinc finger motifs, is rapidly reduced by retinoic acid in F9 teratocarcinoma cells. Molecular and Cellular Biology 9, 5623-5629.
56. Howlett SK 1982 A set of proteins showing cell cycle-dependent modification of the early mouse embryo. Cell 45, 387-396.
57. Huntriss J, Hinkins M, Oliver B et al. 2004 Expression of mRNAs for DNA methyltransferases and methyl-CpG-binding proteins in the human female germ line, preimplantation embryos, and embryonic stem cells. Molecular Reproduction and Development 67, 323-336.
58. Hwang WS, Roh SI, Lee BC et al. 2005 Patient-specific embryonic stem cells derived from human SCNT blastocysts. Science 308, 1777-1783.
59. Islami D, Bischof P, Chardonnens D 2003 Modulation of placental vascular endothelial growth factor by leptin and hCG. Molecular Human Reproduction 9, 395-398.
60. Johnson MH 2003 So what exactly is the role of the spermatozoon in first cleavage? Reproductive BioMedicine Online 6, 163-167.
61. Johnson MH 2002 Time and development. Reproductive BioMedicine Online 4, 140-145.
62. Johnson MH, McConnell JM 2004 Linear allocation and cell polarity during mouse embryogenesis. Seminars in Cell and Developmental Biology 15, 583-597.
63. Kawamura K, Sato N, Fukuda J et al. 2002 Leptin promotes the development of mouse preimplantation embryos in vitro. Endocrinology 143, 1922-1931.
64. Keefe D, Liu L, Wang G, Silva C 2003 Imaging meiotic spindles by polarization light microscopy: principles and applications to IVF. Reproductive BioMedicine Online 7, 24-29.
65. Kelly SJ 1977 Studies of the developmental potential of 4 and 8-cell mouse blastomeres. Journal of Experimental Zoology 200, 365-376.
66. Kennerdell JR, Carthew RW 1998 Use of dsRNA-mediated genetic interference to demonstrate that frizzled and frizzled 2 act in the Wingless pathway. Cell 95, 1017-1026.
67. Ko MSH 2005 Molecular biology of preimplantation embryos: primer for philosophical discussion. Reproductive BioMedicine Online, Suppl. 1, 80-87.
68. Kunarth T, Strumpf D, Rossant J, Tanaka S 2001 Trophoblast stem cells. In: Marshak DR, Gardner RL, Gottlieb D (eds) Stem Cell Biology. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, pp. 267-288.
69. Kusakabe M, Nishida E 2004 The polarity-inducing kinase Par-1 controls Xenopus gastrulation in coopoeration with 14-3-3 and sPKC. EMBO Journal 23, 4190-4201.
70. Lewis WH, Wright ES 1935 On the early development of the mouse egg. Contributions to Embryology 25, 115-143.
71. Lim LP, Lau NC, Garrett-Engele P et al. 2005 Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433, 769-773.
72. Lindeberg M, Hovatta O, Ährlund-Richter L 2004 Real-time reverse transcription-polymerase chain reaction analysis of translation initiation factor 1A (eIF-1A) in human and mouse preimplantation embryos. Reproductive BioMedicine Online 8, 338-343.
73. Liu L, Roberts RM 1996 Silencing of the gene for the beta subunit of human chorionic gonadotropin by the embryonic transcription factor Oct-3/4. Journal of Biological Chemistry 271, 16683-16689.
74. Louvet-Vallée S, Vinot S, Maro B 2005 Mitotic spindles and cleavage planes are oriented randomly in the two-cell mouse embryo. Current Biology 15, 464-469.
75. Lu C, Tej SS, Luo S et al. 2005 Elucidation of the small RNA component of the transcriptome. Science 309, 1567-1569.
76. Mak W, Baxter J, Silva J et al. 2002 Mitotically stable association of polycomb group proteins Eed and Enx 1 with the inactive X chromosome in trophoblast stem cells. Current Biology 12, 1016-1020.
77. Mazet F, Shimeld SM 2003 Characterisation of the amphioxus Fringe gene and the evolution of the vertebrate segmentation clock. Development Genes and Evolution 213, 505-509.
78. Menicucci A, Noci I, Fuzzi B et al. 1999 Non-classic sHLA class I in human oocyte culture medium. Human Immunology 60, 1054-1057.
79. Mikkelesen AL 2005 Strategies in human in-vitro maturation and their clinical outcome. Reproductive BioMedicine Online 10, 593-599.
80. Mitsui K, Tokuzawa Y, Itoh H et al. 2003 The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113, 631-642.
81. Montgomery MK, Xu S, Fire A 1998 RNA as a target of double-stranded RNA-mediated genetic interference in Caenorhbditis elegans. Proceedings of the National Academy of Sciences, USA 95, 15502-15507.
82. Motosugi N, Bauer T, Polanski Z et al. 2005 Polarity of the mouse embryo is established at blastocyst and is not prepatterned. Genes and Development 19, 1080-1092.
83. Munné S, Sandalinas M, Escudero T et al. 2003 Improved implantation after preimplantation genetic diagnosis for aneuploidies. Reproductive BioMedicine Online 7, 91-97.
84. Nagy A, Rossant J, Nagy R et al. 1993 Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proceedings of the National Academy of Sciences USA 90, 8424-8428.
85. Nagy A, Gocza E, Diaz EM 1990 Embryonic stem cells alone are able to support fetal development in the mouse. Development 110, 815-821.
86. Niwa H, Miyazaki J, Smith AG 2000 Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nature Genetics 24, 372-376.
87. Ohlsson R, Larsson E, Nilsson O et al. 1989 Blastocyst implantation precedes induction of insulin-like growth factor II gene expression in human trophoblasts. Development 106, 555-559.
88. Ossipva O, Dhawan S, Sokol S, Green JB 2005 Distinct PAR-1 proteins function in different branches of Wnt signalling during vertebrate development. Developmental Cell 8, 829-841.
89. Pal-Bhadra M, Bhadra U, Birchler JA 2000 Cosuppression of nonhomologous transgenes in Drosophila involves mutually related endogenous sequences. Cell 99, 35-46.
90. Palena H, Mangiacasale R, Magneno AR 2000 E2F transcription factors are differently expressed in murine gametes and early embryos. Mechanisms in Development 97, 211-215.
91. Panáková D, Sprong H, Marois E et al. 2005 Lipoproteins are required for Hedgehog and Wingless signalling. Nature 435, 34-35.
92. Piko L, Clegg KB 1982 Quantitative changes in total RNA, total poly(A) and ribosomes in early more embryos. Developmental Biology 89, 362-378.
93. Piko L, Matsumoto L 1976 Number of mitochondria and some properties of mitochondrial DNA in the mouse egg. Developmental Biology 49, 1-10.
94. Piotrowska K, Zernicke-Goetze M 2002 Early patterning of the mouse embryo: contributions of sperm and egg. Development 129, 5803-5813.
95. Piotrowska K, Wianny E, Pedersen RA, Zernicke-Goetz M 2001 Blastomeres arising from the first cleavage division have distinguishable fates in normal mouse development. Development 128, 3739-3748.
96. Piotrowska-Nitsche K, Zernicka-Goetz M 2005 Spatial arrangement of individual 4-cell stage blastomeres and the order in which they are generated correlate with blastocyst pattern in the mouse embryo. Mechanisms of Development, corrected proof in press.
97. Piotrowska-Nitsche K, Perea-Gomez A, Haraguchi S et al. 2005 Four-cell stage mouse blastomeres have different developmental properties. Development 132, 479-490.
98. Pittoggi G, Zaccagnini C, Giordiani R 2001 Nucleosomal domains of mouse spermatozoa and chromatin as potential sites for retroposition and foreign DNA integration. Molecular Reproduction and Development 56, 248-251.
99. Plusa B, Frankenberg S, Chalmers A et al. 2005 Downregulation of Par 3 and aPKC function directs cells towards the ICM in the preimplantation mouse embryo. Journal of Cell Science 118, 505-515.
100. Rosner MH, Vigano MA, Ozato K et al. 1990 A POU-domain transcription factor in early stem cells and germ cells of the mammalian embryo. Nature 345, 686-692.
101. Rothstein H, Johnson D, DeLoia JA et al. 1992 Gene expression during mouse preimplantation development. Genes and Development 6, 1190-1201.
102. Sathananthan H, Menezes J, Gunasheela S 2003 Mechanics of human blastocyst hatching in vitro. Reproductive BioMedicine Online 7, 228-234.
103. Sato N, Meijer L, Skaltsounis L et al. 2004 Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nature Medicine 10, 55-63.
104. Schöler HR, Dressler GR, Balling R et al. 1990 Oct-4: a germline-specific transcription factor mapping to the mouse t-complex. EMBO Journal 9, 2185-2195.
105. Seidel F 1952 Die Entwickslungspotenzen einer isolierten Blastomere des Zweizellenstadiums im Saugeterei. Naturwissenschaften 39, 355-356.
106. Sharov AA, Piao Y, Matoba R et al. 2003 Transcriptome analysis of mouse stem cells and early embryos. Public Library of Science Biology 1, E74.
107. Sher G, Keskintepe L, Nouriani M et al. 2004 Expression of sHLA-G in supernatants of individually cultured 46-h embryos: a potentially valuable indicator of 'embryo competency' and IVF outcome. Reproductive BioMedicine Online 9, 74-78.
108. Skarnes WC, Auerbach BA, Joyner AC 1992 A gene trap approach in mouse embryonic stem cells: the lacZ reported is activated by splicing, reflects endogenous gene expression, and is mutagenic in mice. Genes and Development 6, 903-918.
109. Sokac AM, Co C, Taunton J, Bement L 2003 Cdc42-dependent actin polymerization during compensatory endocytosis in Xenopus eggs. Nature Cell Biology 5, 727-732.
110. Sönnischen B, Koski LB, Walsh A et al. 2005 Full-genome RNAi profiling of early embryogenesis in Caenorhabditis elegans. Nature 434, 462-469.
111. Spemann H, Mangold H 1924 Über Induktion von Embryonalanlagen durch Implantation artfremder Organisatoren. Archiv für Mikroskopische Anatomie und Entwicklungsmechanik 100, 599-638.
112. Strumpf D, Mao CA, Yamanaka Y et al. 2005 Cdx2 is required for correct fate specification and differentiation of trophectoderm in the mouse blastocyst. Development 132, 2093-2102.
113. Suh M-R, Lee Y, Kim JY et al. 2004 Human embryonic stem cells express a unique set of microRNAS. Developmental Biology 270, 488-498.
114. Svoboda P, Stein P, Hayashi H, Schultz RM. 2000 Selective reduction of dormant maternal RNAs in mouse oocytes by RNA interference. Development 127, 4147-4193.
115. Tanaka S, Kunath T, Hadjantonakis AK et al. 1998 Promotion of trophoblast stem cell proliferation by FGF4. Science 282, 2072-2075.
116. Tarkowski AK 1959 Experimental studies on regulation in the development of isolated blastomeres of mouse eggs. Acta Theriologie 3, 191-267.
117. Tarkowski AK, Wroblewska J 1967 Development of blastomeres of mouse eggs isolated at the 4- and 8-cell stage. Journal of Embryology and Developmental Morphology 18, 155-180.
118. Tavernarakis N, Wang SL, Dorovkov M et al. 2000 Heritable and inducible genetic interference by double-stranded RNA encoded by transgenes. Nature Genetics 24, 180-183.
119. Tesarik J 1988 Early morphological signs of embryonic genome expression in human preimplantation development as revealed by quantitative electron microscopy. Developmental Biology 128, 15-20.
120. Thompson EM, Legouy E, Renard JP 1998 Mouse embryos do not wait for the MBT: chromatin and RNA polymerase remodeling in genome activation at the onset of development. Developmental Genetics 22, 31-42.
121. Tong ZB, Gold L, Pfeifer KE et al. 2000 Mater, a maternal effect gene required for early embryonic development in mice. Nature Genetics 26, 267-268.
122. Vinot S, Le Tran, Maro B, Louvet-Vallée S 2004 Two PAR6 proteins become asymmetrically localized during establishment of polarity in mouse oocytes. Current Biology 14, 520-525.
123. Wang Z, Jaenisch R 2004 At most three ES cells contribute to the somatic lineages of chimeric mice and of mice produced by ES-tetraploid complementation. Developmental Biology 275, 192-201.
124. Welsh J, Liu JP, Efstratiadis A 1990 Cloning of PCR-amplified total cDNA: construction of a mouse oocyte cDNA library. Genetic Analysis Techniques and Amplifications 7, 5-17.
125. Wianny F, Zernica-Goetz M 2000 Specific interference with gene function by double-stranded RNA in early mouse development. Nature Cell Biology 2, 70-75.
126. Zamore PD, Tuschi T, Sharp PA, Bartel DP 2000 RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals. Cell 101, 25-33.
127. Zernicka-Goetz M 2003 Determining the first cleavage of the mouse zygote. Reproductive BioMedicine Online 6, 160-163.
128. Zernicka-Goetz M 1998 Fertile offspring derived from mammalian eggs lacking either animal or vegetal poles. Development 125, 4803-4808.
129. Zhao Y, Samai E, Srivastava D 2005 Serum response factor regulates a muscle-specific microRNA that targets hand 2 during cardiogensis. Nature 436, 234-236.