Flow-induced protein kinase A-CREB pathway acts via BMP signaling to promote HSC emergence

Journal of Experimental Medicine

Volumn 212, Issue 5, 2015, Pages 633-648

  Kim, Peter Geon ^a,b,c   Nakano, Haruko ^d   Das, Partha P ^a   Chen, Michael J ^a,b,c   Rowe, R Grant ^a,b,c   Chou, Stephanie S ^a,b,c   Ross, Samantha J ^a,b,c   Sakamoto, Kathleen M ^e   Zon, Leonard I ^a,b,c   Schlaeger, Thorsten M ^a,b,c   Orkin, Stuart H ^a   Nakano, Atsushi ^d   Daley, George Q ^a,b,c  

^a HARVARD STEM CELL INSTITUTE   (United States)

^b BOSTON CHILDREN S HOSPITAL   (United States)

^c HARVARD MEDICAL SCHOOL   (United States)

^d UNIVERSITY OF CALIFORNIA   (United States)

^e LUCILE PACKARD CHILDREN S HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BONE MORPHOGENETIC PROTEIN; CYCLIC AMP DEPENDENT PROTEIN KINASE; CYCLIC AMP RESPONSIVE ELEMENT BINDING PROTEIN; CREB1 PROTEIN, MOUSE; NCX1 PROTEIN, MOUSE; SODIUM CALCIUM EXCHANGE PROTEIN;

ANIMAL TISSUE; AORTA GONAD MESONEPHROS; ARTICLE; BLOOD FLOW; CHROMATIN IMMUNOPRECIPITATION; CONTROLLED STUDY; EMBRYO; GENE EXPRESSION; HEMATOPOIETIC STEM CELL; HUMAN; HUMAN CELL; MESONEPHROS; MOUSE; NONHUMAN; NUCLEOTIDE SEQUENCE; PRIORITY JOURNAL; SHEAR STRESS; SIGNAL TRANSDUCTION; ANIMAL; ANIMAL EMBRYO; CYTOLOGY; EMBRYOLOGY; ENDOTHELIUM CELL; GENETICS; METABOLISM; MUTANT MOUSE STRAIN; PHYSIOLOGY;

ANIMALS; BONE MORPHOGENETIC PROTEINS; CYCLIC AMP RESPONSE ELEMENT-BINDING PROTEIN; CYCLIC AMP-DEPENDENT PROTEIN KINASES; EMBRYO, MAMMALIAN; ENDOTHELIAL CELLS; HEMATOPOIETIC STEM CELLS; MESONEPHROS; MICE; MICE, MUTANT STRAINS; SIGNAL TRANSDUCTION; SODIUM-CALCIUM EXCHANGER;

EID: 84946416387     PISSN: 00221007     EISSN: 15409538     Source Type: Journal    
DOI: 10.1084/jem.20141514     Document Type: Article

References (71)

1. Adamo, L., O. Naveiras, P.L. Wenzel, S. McKinney-Freeman, P.J. Mack, J. Gracia-Sancho, A. Suchy-Dicey, M. Yoshimoto, M.W. Lensch, M.C. Yoder, et al. 2009. Biomechanical forces promote embryonic haematopoiesis. Nature. 459:1131-1135. http://dx.doi.org/10.1038/nature08073
2. Alfranca, A., M.A. I-iguez, M. Fresno, and J.M. Redondo. 2006. Prostanoid signal transduction and gene expression in the endothelium: role in cardiovascular diseases. Cardiovasc. Res. 70:446-456. http://dx.doi.org/10.1016/j.cardiores.2005.12.020
3. Arora, N., P.L. Wenzel, S.L. McKinney-Freeman, S.J. Ross, P.G. Kim, S.S. Chou, M. Yoshimoto, M.C. Yoder, and G.Q. Daley. 2014. Effect of developmental stage of HSC and recipient on transplant outcomes. Dev. Cell. 29:621-628. http://dx.doi.org/10.1016/j.devcel.2014.04.013
4. Barski, A., S. Cuddapah, K. Cui, T.Y. Roh, D.E. Schones, Z. Wang, G. Wei, I. Chepelev, and K. Zhao. 2007. High-resolution profiling of histone methylations in the human genome. Cell. 129:823-837. http://dx.doi.org/10.1016/j.cell.2007.05.009
5. Bertrand, J.Y., N.C. Chi, B. Santoso, S. Teng, D.Y. Stainier, and D. Traver. 2010. Haematopoietic stem cells derive directly from aortic endothelium during development. Nature. 464:108-111. http://dx.doi.org/10.1038/nature08738
6. Boisset, J.C., W. van Cappellen, C. Andrieu-Soler, N. Galjart, E. Dzierzak, and C. Robin. 2010. In vivo imaging of haematopoietic cells emerging from the mouse aortic endothelium. Nature. 464:116-120. http://dx.doi.org/10.1038/nature08764
7. Bolstad, B.M., R.A. Irizarry, M. Astrand, and T.P. Speed. 2003. A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics. 19:185-193. http://dx .doi.org/10.1093/bioinformatics/19.2.185
8. Carpenter, A.E., T.R. Jones, M.R. Lamprecht, C. Clarke, I.H. Kang, O. Friman, D.A. Guertin, J.H. Chang, R.A. Lindquist, J. Moffat, et al. 2006. CellProfiler: image analysis software for identifying and quantifying cell phenotypes. Genome Biol. 7:R100. http://dx.doi.org/10.1186/gb-2006-7-10-r100
9. Chanda, B., A. Ditadi, N.N. Iscove, and G. Keller. 2013. Retinoic acid signaling is essential for embryonic hematopoietic stem cell development. Cell. 155:215-227. http://dx.doi.org/10.1016/j.cell.2013.08.055
10. Chen, C.R., Y. Kang, P.M. Siegel, and J. Massagu-. 2002. E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression. Cell. 110:19-32. http://dx.doi.org/10.1016/S0092-8674(02)00801-2
11. Chen, M.J., T. Yokomizo, B.M. Zeigler, E. Dzierzak, and N.A. Speck. 2009. Runx1 is required for the endothelial to haematopoietic cell transition but not thereafter. Nature. 457:887-891. http://dx.doi.org/10.1038/nature07619
12. Chen, M.J., Y. Li, M.E. De Obaldia, Q. Yang, A.D. Yzaguirre, T. Yamada-Inagawa, C.S. Vink, A. Bhandoola, E. Dzierzak, and N.A. Speck. 2011. Erythroid/myeloid progenitors and hematopoietic stem cells originate from distinct populations of endothelial cells. Cell Stem Cell. 9:541-552. http://dx.doi.org/10.1016/j.stem.2011.10.003
13. Cherian, P.P., B. Cheng, S. Gu, E. Sprague, L.F. Bonewald, and J.X. Jiang. 2003. Effects of mechanical strain on the function of Gap junctions in osteocytes are mediated through the prostaglandin EP2 receptor. J. Biol. Chem. 278:43146-43156. http://dx.doi.org/10.1074/jbc.M302993200
14. Creyghton, M.P., A.W. Cheng, G.G. Welstead, T. Kooistra, B.W. Carey, E.J. Steine, J. Hanna, M.A. Lodato, G.M. Frampton, P.A. Sharp, et al. 2010. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc. Natl. Acad. Sci. USA. 107:21931-21936. http://dx.doi.org/10.1073/pnas.1016071107
15. Davies, S.P., H. Reddy, M. Caivano, and P. Cohen. 2000. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem. J. 351:95-105. http://dx.doi.org/10.1042/0264-6021: 3510095
16. de Bruijn, M.F., X. Ma, C. Robin, K. Ottersbach, M.J. Sanchez, and E. Dzierzak. 2002. Hematopoietic stem cells localize to the endothelial cell layer in the midgestation mouse aorta. Immunity. 16:673-683. http://dx.doi.org/10.1016/S1074-7613(02)00313-8
17. de Rooij, J., F.J. Zwartkruis, M.H. Verheijen, R.H. Cool, S.M. Nijman, A. Wittinghofer, and J.L. Bos. 1998. Epac is a Rap1 guanine-nucleotideexchange factor directly activated by cyclic AMP. Nature. 396:474-477. http://dx.doi.org/10.1038/24884
18. Dela Paz, N.G., T.E. Walshe, L.L. Leach, M. Saint-Geniez, and P.A. D-Amore. 2012. Role of shear-stress-induced VEGF expression in endothelial cell survival. J. Cell Sci. 125:831-843. http://dx.doi.org/10.1242/jcs.084301
19. Durand, C., C. Robin, K. Bollerot, M.H. Baron, K. Ottersbach, and E. Dzierzak. 2007. Embryonic stromal clones reveal developmental regulators of definitive hematopoietic stem cells. Proc. Natl. Acad. Sci. USA. 104:20838-20843. http://dx.doi.org/10.1073/pnas.0706923105
20. Esparza, S.D., J. Chang, D.B. Shankar, B. Zhang, S.F. Nelson, and K.M. Sakamoto. 2008. CREB regulates Meis1 expression in normal and malignant hematopoietic cells. Leukemia. 22:665-667. http://dx.doi.org/10 .1038/sj.leu.2404933
21. Ficara, F., M.J. Murphy, M. Lin, and M.L. Cleary. 2008. Pbx1 regulates self-renewal of long-term hematopoietic stem cells by maintaining their quiescence. Cell Stem Cell. 2:484-496. http://dx.doi.org/10.1016/j.stem .2008.03.004
22. Fitch, S.R., G.M. Kimber, N.K. Wilson, A. Parker, B. Mirshekar-Syahkal, B. G-ttgens, A. Medvinsky, E. Dzierzak, and K. Ottersbach. 2012. Signaling from the sympathetic nervous system regulates hematopoietic stem cell emergence during embryogenesis. Cell Stem Cell. 11:554-566. http://dx.doi.org/10.1016/j.stem.2012.07.002
23. Goessling, W., T.E. North, S. Loewer, A.M. Lord, S. Lee, C.L. Stoick-Cooper, G. Weidinger, M. Puder, G.Q. Daley, R.T. Moon, and L.I. Zon. 2009. Genetic interaction of PGE2 and Wnt signaling regulates developmental specification of stem cells and regeneration. Cell. 136:1136-1147. http://dx.doi.org/10.1016/j.cell.2009.01.015
24. Goessling, W., R.S. Allen, X. Guan, P. Jin, N. Uchida, M. Dovey, J.M. Harris, M.E. Metzger, A.C. Bonifacino, D. Stroncek, et al. 2011. Prostaglandin E2 enhances human cord blood stem cell xenotransplants and shows long-term safety in preclinical nonhuman primate transplant models. Cell Stem Cell. 8:445-458. http://dx.doi.org/10.1016/j.stem.2011.02 .003
25. Gonzalez, G.A., and M.R. Montminy. 1989. Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell. 59:675-680. http://dx.doi.org/10.1016/0092-8674(89)90013-5
26. Hino, S., C. Tanji, K.I. Nakayama, and A. Kikuchi. 2005. Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase stabilizes betacatenin through inhibition of its ubiquitination. Mol. Cell. Biol. 25:9063- 9072. http://dx.doi.org/10.1128/MCB.25.20.9063-9072.2005
27. Irizarry, R.A., B. Hobbs, F. Collin, Y.D. Beazer-Barclay, K.J. Antonellis, U. Scherf, and T.P. Speed. 2003. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics. 4:249-264. http://dx.doi.org/10.1093/biostatistics/4.2.249
28. Jang, I.H., Y.F. Lu, L. Zhao, P.L. Wenzel, T. Kume, S.M. Datta, N. Arora, J. Guiu, M. Lagha, P.G. Kim, et al. 2015. Notch1 acts via Foxc2 to promote definitive hematopoiesis via effects on hemogenic endothelium. Blood. 125:1418-1426. http://dx.doi.org/10.1182/blood-2014-04-568170
29. Ji, R.P., C.K. Phoon, O. Aristiz-bal, K.E. McGrath, J. Palis, and D.H. Turnbull. 2003. Onset of cardiac function during early mouse embryogenesis coincides with entry of primitive erythroblasts into the embryo proper. Circ. Res. 92:133-135. http://dx.doi.org/10.1161/01.RES .0000056532.18710.C0
30. Jolma, A., T. Kivioja, J. Toivonen, L. Cheng, G. Wei, M. Enge, M. Taipale, J.M. Vaquerizas, J. Yan, M.J. Sillanp--, et al. 2010. Multiplexed massively parallel SELEX for characterization of human transcription factor binding specificities. Genome Res. 20:861-873. http://dx.doi.org/10.1101/gr.100552.109
31. Kennedy, M., G. Awong, C.M. Sturgeon, A. Ditadi, R. LaMotte-Mohs, J.C. Zúñiga-Pflücker, and G. Keller. 2012. T lymphocyte potential marks the emergence of definitive hematopoietic progenitors in human pluripotent stem cell differentiation cultures. Cell Reports. 2:1722-1735. http://dx.doi.org/10.1016/j.celrep.2012.11.003
32. Kim, P.G., C.E. Albacker, Y.F. Lu, I.H. Jang, Y. Lim, G.C. Heffner, N. Arora, T.V. Bowman, M.I. Lin, M.W. Lensch, et al. 2013. Signaling axis involving Hedgehog, Notch, and Scl promotes the embryonic endothelial-to-hematopoietic transition. Proc. Natl. Acad. Sci. USA. 110:E141-E150. http://dx.doi.org/10.1073/pnas.1214361110
33. Koch, C.M., R.M. Andrews, P. Flicek, S.C. Dillon, U. Kara-z, G.K. Clelland, S. Wilcox, D.M. Beare, J.C. Fowler, P. Couttet, et al. 2007. The landscape of histone modifications across 1% of the human genome in five human cell lines. Genome Res. 17:691-707. http://dx.doi .org/10.1101/gr.5704207
34. Koushik, S.V., J. Wang, R. Rogers, D. Moskophidis, N.A. Lambert, T.L. Creazzo, and S.J. Conway. 2001. Targeted inactivation of the sodiumcalcium exchanger (Ncx1) results in the lack of a heartbeat and abnormal myofibrillar organization. FASEB J. 15:1209-1211.
35. Kretzschmar, M., F. Liu, A. Hata, J. Doody, and J. Massagu-. 1997. The TGF-beta family mediator Smad1 is phosphorylated directly and activated functionally by the BMP receptor kinase. Genes Dev. 11:984-995. http://dx.doi.org/10.1101/gad.11.8.984
36. Langmead, B., C. Trapnell, M. Pop, and S.L. Salzberg. 2009. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10:R25. http://dx.doi.org/10.1186/gb-2009-10-3-r25
37. Ley, K., E. Lundgren, E. Berger, and K.E. Arfors. 1989. Shear-dependent inhibition of granulocyte adhesion to cultured endothelium by dextran sulfate. Blood. 73:1324-1330.
38. Ling, K.W., K. Ottersbach, J.P. van Hamburg, A. Oziemlak, F.Y. Tsai, S.H. Orkin, R. Ploemacher, R.W. Hendriks, and E. Dzierzak. 2004. GATA-2 plays two functionally distinct roles during the ontogeny of hematopoietic stem cells. J. Exp. Med. 200:871-882. http://dx.doi.org/10.1084/jem.20031556
39. Liu, L., Y. Wang, Y. Fan, C.L. Li, and Z.L. Chang. 2004. IFN-gamma activates cAMP/PKA/CREB signaling pathway in murine peritoneal macrophages. J. Interferon Cytokine Res. 24:334-342.
40. Lux, C.T., M. Yoshimoto, K. McGrath, S.J. Conway, J. Palis, and M.C. Yoder. 2008. All primitive and definitive hematopoietic progenitor cells emerging before E10 in the mouse embryo are products of the yolk sac. Blood. 111:3435-3438. http://dx.doi.org/10.1182/blood-2007-08-107086
41. Lyden, D., A.Z. Young, D. Zagzag, W. Yan, W. Gerald, R. O-Reilly, B.L. Bader, R.O. Hynes, Y. Zhuang, K. Manova, and R. Benezra. 1999. Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts. Nature. 401:670-677. http://dx.doi.org/10 .1038/44334
42. Marshall, C.J., J.C. Sinclair, A.J. Thrasher, and C. Kinnon. 2007. Bone morphogenetic protein 4 modulates c-Kit expression and differentiation potential in murine embryonic aorta-gonad-mesonephros haematopoiesis in vitro. Br. J. Haematol. 139:321-330. http://dx.doi.org/10.1111/j.1365-2141.2007.06795.x
43. Martens, J.H., A. Mandoli, F. Simmer, B.J. Wierenga, S. Saeed, A.A. Singh, L. Altucci, E. Vellenga, and H.G. Stunnenberg. 2012. ERG and FLI1 binding sites demarcate targets for aberrant epigenetic regulation by AML1-ETO in acute myeloid leukemia. Blood. 120:4038-4048. http://dx.doi.org/10.1182/blood-2012-05-429050
44. McKinney-Freeman, S., P. Cahan, H. Li, S.A. Lacadie, H.T. Huang, M. Curran, S. Loewer, O. Naveiras, K.L. Kathrein, M. Konantz, et al. 2012. The transcriptional landscape of hematopoietic stem cell ontogeny. Cell Stem Cell. 11:701-714. http://dx.doi.org/10.1016/j.stem.2012.07.018
45. Medvinsky, A., and E. Dzierzak. 1996. Definitive hematopoiesis is autonomously initiated by the AGM region. Cell. 86:897-906. http://dx.doi .org/10.1016/S0092-8674(00)80165-8
46. Mi, H., N. Guo, A. Kejariwal, and P.D. Thomas. 2007. PANTHER version 6: protein sequence and function evolution data with expanded representation of biological pathways. Nucleic Acids Res. 35(Database):D247- D252. http://dx.doi.org/10.1093/nar/gkl869
47. Moore, M.A., and D. Metcalf. 1970. Ontogeny of the haemopoietic system: yolk sac origin of in vivo and in vitro colony forming cells in the developing mouse embryo. Br. J. Haematol. 18:279-296. http://dx.doi. org/10.1111/j.1365-2141.1970.tb01443.x
48. Nagase, T., M. Nagase, K. Yoshimura, M. Machida, and M. Yamagishi. 2006. Defects in aortic fusion and craniofacial vasculature in the holoprosencephalic mouse embryo under inhibition of sonic hedgehog signaling. J. Craniofac. Surg. 17:736-744. http://dx.doi.org/10.1097/00001665-200607000-00026
49. Ni, C.W., H. Qiu, and H. Jo. 2011. MicroRNA-663 upregulated by oscillatory shear stress plays a role in inflammatory response of endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 300:H1762-H1769. http://dx.doi .org/10.1152/ajpheart.00829.2010
50. North, T.E., M.F. de Bruijn, T. Stacy, L. Talebian, E. Lind, C. Robin, M. Binder, E. Dzierzak, and N.A. Speck. 2002. Runx1 expression marks long-term repopulating hematopoietic stem cells in the midgestation mouse embryo. Immunity. 16:661-672. http://dx.doi.org/10.1016/S1074-7613(02)00296-0
51. North, T.E., W. Goessling, M. Peeters, P. Li, C. Ceol, A.M. Lord, G.J. Weber, J. Harris, C.C. Cutting, P. Huang, et al. 2009. Hematopoietic stem cell development is dependent on blood flow. Cell. 137:736-748. http://dx.doi.org/10.1016/j.cell.2009.04.023
52. Ogawa, H., E. Kozhemyakina, H.H. Hung, A.J. Grodzinsky, and A.B. Lassar. 2014. Mechanical motion promotes expression of Prg4 in articular cartilage via multiple CREB-dependent, fluid flow shear stressinduced signaling pathways. Genes Dev. 28:127-139. http://dx.doi.org/10.1101/gad.231969.113
53. Pencovich, N., R. Jaschek, A. Tanay, and Y. Groner. 2011. Dynamic combinatorial interactions of RUNX1 and cooperating partners regulates megakaryocytic differentiation in cell line models. Blood. 117:e1-e14. http://dx.doi.org/10.1182/blood-2010-07-295113
54. Pereira, C.F., B. Chang, J. Qiu, X. Niu, D. Papatsenko, C.E. Hendry, N.R. Clark, A. Nomura-Kitabayashi, J.C. Kovacic, A. Ma-ayan, et al. 2013. Induction of a hemogenic program in mouse fibroblasts. Cell Stem Cell. 13:205-218. http://dx.doi.org/10.1016/j.stem.2013.05.024
55. Raney, B.J., M.S. Cline, K.R. Rosenbloom, T.R. Dreszer, K. Learned, G.P. Barber, L.R. Meyer, C.A. Sloan, V.S. Malladi, K.M. Roskin, et al. 2011. ENCODE whole-genome data in the UCSC genome browser (2011 update). Nucleic Acids Res. 39(Database):D871-D875. http://dx.doi.org/10.1093/nar/gkq1017
56. Ruiz-Herguido, C., J. Guiu, T. D-Altri, J. Ingl-s-Esteve, E. Dzierzak, L. Espinosa, and A. Bigas. 2012. Hematopoietic stem cell development requires transient Wnt/?-catenin activity. J. Exp. Med. 209:1457-1468. http://dx.doi.org/10.1084/jem.20120225
57. Swiers, G., C. Baumann, J. O-Rourke, E. Giannoulatou, S. Taylor, A. Joshi, V. Moignard, C. Pina, T. Bee, K.D. Kokkaliaris, et al. 2013. Early dynamic fate changes in haemogenic endothelium characterized at the single-cell level. Nat. Commun. 4:2924. http://dx.doi.org/10.1038/ncomms3924
58. Taoudi, S., C. Gonneau, K. Moore, J.M. Sheridan, C.C. Blackburn, E. Taylor, and A. Medvinsky. 2008. Extensive hematopoietic stem cell generation in the AGM region via maturation of VE-cadherin+CD45+ pre-definitive HSCs. Cell Stem Cell. 3:99-108. http://dx.doi.org/10 .1016/j.stem.2008.06.004
59. Thorvaldsd-ttir, H., J.T. Robinson, and J.P. Mesirov. 2013. Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration. Brief. Bioinform. 14:178-192. http://dx.doi.org/10 .1093/bib/bbs017
60. Trompouki, E., T.V. Bowman, L.N. Lawton, Z.P. Fan, D.C. Wu, A. DiBiase, C.S. Martin, J.N. Cech, A.K. Sessa, J.L. Leblanc, et al. 2011. Lineage regulators direct BMP and Wnt pathways to cell-specific programs during differentiation and regeneration. Cell. 147:577-589. http://dx.doi.org/10.1016/j.cell.2011.09.044
61. Vermot, J., A.S. Forouhar, M. Liebling, D. Wu, D. Plummer, M. Gharib, and S.E. Fraser. 2009. Reversing blood flows act through klf2a to ensure normal valvulogenesis in the developing heart. PLoS Biol. 7:e1000246. http://dx.doi.org/10.1371/journal.pbio.1000246
62. Wang, L., P. Zhang, Y. Wei, Y. Gao, R. Patient, and F. Liu. 2011. A blood flow-dependent klf2a-NO signaling cascade is required for stabilization of hematopoietic stem cell programming in zebrafish embryos. Blood. 118:4102-4110. http://dx.doi.org/10.1182/blood-2011-05-353235
63. Wilkinson, R.N., C. Pouget, M. Gering, A.J. Russell, S.G. Davies, D. Kimelman, and R. Patient. 2009. Hedgehog and Bmp polarize hematopoietic stem cell emergence in the zebrafish dorsal aorta. Dev. Cell. 16:909-916. http://dx.doi.org/10.1016/j.devcel.2009.04.014
64. Wilson, B.E., E. Mochon, and L.M. Boxer. 1996. Induction of bcl-2 expression by phosphorylated CREB proteins during B-cell activation and rescue from apoptosis. Mol. Cell. Biol. 16:5546-5556.
65. Yamamizu, K., T. Matsunaga, S. Katayama, H. Kataoka, N. Takayama, K. Eto, S. Nishikawa, and J.K. Yamashita. 2012. PKA/CREB signaling triggers initiation of endothelial and hematopoietic cell differentiation via Etv2 induction. Stem Cells. 30:687-696. http://dx.doi.org/10.1002/stem.1041
66. Yoder, M.C., K. Hiatt, P. Dutt, P. Mukherjee, D.M. Bodine, and D. Orlic. 1997. Characterization of definitive lymphohematopoietic stem cells in the day 9 murine yolk sac. Immunity. 7:335-344. http://dx.doi.org/10 .1016/S1074-7613(00)80355-6
67. Yu, P.B., D.Y. Deng, C.S. Lai, C.C. Hong, G.D. Cuny, M.L. Bouxsein, D.W. Hong, P.M. McManus, T. Katagiri, C. Sachidanandan, et al. 2008a. BMP type I receptor inhibition reduces heterotopic [corrected] ossification. Nat. Med. 14:1363-1369. http://dx.doi.org/10.1038/nm.1888
68. Yu, P.B., C.C. Hong, C. Sachidanandan, J.L. Babitt, D.Y. Deng, S.A. Hoyng, H.Y. Lin, K.D. Bloch, and R.T. Peterson. 2008b. Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat. Chem. Biol. 4:33-41. http://dx.doi.org/10.1038/nchembio.2007.54
69. Zhang, X., D.T. Odom, S.H. Koo, M.D. Conkright, G. Canettieri, J. Best, H. Chen, R. Jenner, E. Herbolsheimer, E. Jacobsen, et al. 2005. Genomewide analysis of cAMP-response element binding protein occupancy, phosphorylation, and target gene activation in human tissues. Proc. Natl. Acad. Sci. USA. 102:4459-4464. http://dx.doi.org/10.1073/pnas.0501076102
70. Zhang, Y., T. Liu, C.A. Meyer, J. Eeckhoute, D.S. Johnson, B.E. Bernstein, C. Nusbaum, R.M. Myers, M. Brown, W. Li, and X.S. Liu. 2008. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9:R137. http://dx.doi.org/10.1186/gb-2008-9-9-r137
71. Zhang, R., J.R. Edwards, S.Y. Ko, S. Dong, H. Liu, B.O. Oyajobi, C. Papasian, H.W. Deng, and M. Zhao. 2011. Transcriptional regulation of BMP2 expression by the PTH-CREB signaling pathway in osteoblasts. PLoS ONE. 6:e20780. http://dx.doi.org/10.1371/journal .pone.0020780