Abstract
Hematopoietic stem cells (HSCs) have a capacity to undergo self-renewal and differentiation into several distinct cell lineages, which maintain blood production and provide mature blood cells throughout life. To clarify molecular mechanisms governing HSC development, we performed a genome-wide gene expression analysis of fetal liver (FL) HSC cDNA library, and identified a novel gene, hemp (h ematopoietic e xpressed m ammalian p olycomb), that encodes a protein with a zinc-finger domain and four malignant brain tumor (mbt) repeats. To elucidate its biological role(s), we generated hemp-deficient mice and found that Hemp plays pivotal roles in HSC function and skeletal formation. Mononuclear cell number in hemp −/− FLs was markedly reduced, and hemp −/− FL HSCs exhibited significant defects in colony-forming and competitive repopulation assays. In addition, hemp −/− embryos exhibited various skeletal malformations, such as a fusion of cervical vertebrae. Since osteoblasts and HSCs coexist in the bone marrow niche and physically and functionally interact with each other, it is suggested that Hemp-mediated signalling positively and coordinately regulates normal development of these types of cells. In addition, skeletal abnormalities detected in hemp −/− mice closely resemble to those observed in human Klippel-Feil anomaly, suggesting that Hemp might be involved in the pathogenesis of this disease.
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References
Arai S, Miyazaki T (2005) Impaired maturation of myeloid progenitors in mice lacking novel Polycomb group protein MBT-1. EMBO J 24:1863–1873
Baga N, Chusid EL, Miller A (1969) Pulmonary disability in the Klippel-Feil syndrome. A study of two siblings. Clin Orthop Relat Res 67:105–110
Berger J, Kurahashi H, Takihara Y, Shimada K, Brock HW, Randazzo F (1999) The human homolog of Sex comb on midleg (SCMH1) maps to chromosome 1p34. Gene 237:185–191
Bonasio R, Lecona E, Reinberg D (2010) MBT domain proteins in development and disease. Semin Cell Dev Biol 21:221–230
Bornemann D, Miller E, Simon J (1996) The Drosophila Polycomb group gene Sex comb on midleg (Scm) encodes a zinc finger protein with similarity to polyhomeotic protein. Development 122:1621–1630
Charles JE, Robert PE, Anthony WB (2008) Inborn errors of development, Secondth edn. Oxford University Press, Oxford
Deneault E, Cellot S, Faubert A, Laverdure JP, Fréchette M, Chagraoui J, Mayotte N, Sauvageau M, Ting SB, Sauvageau G (2009) A functional screen to identify novel effectors of hematopoietic stem cell activity. Cell 137:369–379
Dzierzak E, Speck NA (2008) Of lineage and legacy: the development of mammalian hematopoietic stem cells. Nat Immunol 9:129–136
Eryilmaz J, Pan P, Amaya MF, Allali-Hassani A, Dong A, Adams-Cioaba MA, Mackenzie F, Vedadi M, Min J (2009) Structural studies of a four-MBT repeat protein MBTD1. PLoS One 4:e7274
Fukushima Y, Ohashi H, Wakui K, Nishimoto H, Sato M, Aihara T (1995) De novo apparently balanced reciprocal translocation between 5q11.2 and 17q23 associated with Klippel-Feil anomaly and type A1 brachydactyly. Am J Med Genet 57:447–449
Goto M, Nishimura G, Nagai T, Yamazawa K, Ogata T (2006) Familial Klippel-Feil anomaly and t(5;8)(q35.1;p21.1) translocation. Am J Med Genet A 140:1013–1015
Greenspan A, Cohen J, Szabo RM (1991) Klippel-Feil syndrome. An unusual association with Sprengel deformity, omovertebral bone, and other skeletal, hematologic, and respiratory disorders. A case report. Bull Hosp Jt Dis Orthop Inst 51:54–62
Honda H, Takubo K, Oda H, Kosaki K, Tazaki T, Yamasaki N, Miyazaki K, Moore KA, Honda Z, Suda T, Lemischka IR (2011) Hemp, an mbt domain-containing protein, plays essential roles in hematopoietic stem cell function and skeletal formation. Proc Natl Acad Sci USA 108:2468–2473
Klimo P Jr, Rao G, Brockmeyer D (2007) Congenital anomalies of the cervical spine. Neurosurg Clin N Am 18:463–478
Koga H, Matsui S, Hirota T, Takebayashi S, Okumura K, Saya H (1999) A human homolog of Drosophila lethal(3)malignant brain tumor (l(3)mbt) protein associates with condensed mitotic chromosomes. Oncogene 18:3799–3809
Lazarus KH, McCurdy FA (1984) Multiple congenital anomalies in a patient with- Diamond-Blackfan syndrome. Clin Pediatr (Phila) 23:520–521
Markus J, Feikova S, Sramko M, Wolff L, Bies J (2003) Proliferation-linked expression of the novel murine gene m4mbt encoding a nuclear zinc finger protein with four mbt domains. Gene 319:117–126
McGaughran J (2003) Klippel-Feil anomaly in Fanconi anemia. Clin Dysmorphol 12:197
Montini E, Buchner G, Spalluto C, Andolfi G, Caruso A, den Dunnen JT, Trump D, Rocchi M, Ballabio A, Franco B (1999) Identification of SCML2, a second human gene homologous to the Drosophila sex comb on midleg (Scm): a new gene cluster on Xp22. Genomics 58:65–72
Peterson AJ, Kyba M, Bornemann D, Morgan K, Brock HW, Simon J (1997) A domain shared by the Polycomb group proteins Scm and ph mediates heterotypic and homotypic interactions. Mol Cell Biol 17:6683–6692
Phillips RL, Ernst RE, Brunk B, Ivanova N, Mahan MA, Deanehan JK, Moore KA, Overton GC, Lemischka IR (2000) The genetic program of hematopoietic stem cells. Science 288:1635–1640
Rooryck C, Burgelin I, Stef M, Taine L, Thambo JB, Lacombe D, Arveiler B (2008) A 580 kb microdeletion in 17q21.32 associated with mental retardation, microcephaly, cleft palate, and cardiac malformation. Eur J Med Genet 51:74–80
Smoker WR, Khanna G (2008) Imaging the craniocervical junction. Childs Nerv Syst 24:1123–1145
Usui H, Ichikawa T, Kobayashi K, Kumanishi T (2000) Cloning of a novel murine gene Sfmbt, Scm-related gene containing four mbt domains, structurally belonging to the Polycomb group of genes. Gene 248:127–135
van Lohuizen M (1998) Functional analysis of mouse Polycomb group genes. Cell Mol Life Sci 54:71–79
Wismar J (2001) Molecular characterization of h-l(3)mbt-like: a new member of the human mbt family. FEBS Lett 507:119–121
Wismar J, Loffler T, Habtemichael N, Vef O, Geissen M, Zirwes R, Altmeyer W, Sass H, Gateff E (1995) The Drosophila melanogaster tumor suppressor gene lethal(3)malignant brain tumor encodes a proline-rich protein with a novel zinc finger. Mech Dev 53:141–154
Yue Y, Farcas R, Thiel G, Bommer C, Grossmann B, Galetzka D, Kelbova C, Küpferling P, Daser A, Zechner U, Haaf T (2007) De novo t(12;17)(p13.3;q21.3) translocation with a breakpoint near the 5′ end of the HOXB gene cluster in a patient with developmental delay and skeletal malformations. Eur J Hum Genet 15:570–577
Zahir FR, Langlois S, Gall K, Eydoux P, Marra MA, Friedman JM (2009) A novel de novo 1.1 Mb duplication of 17q21.33 associated with cognitive impairment and other anomalies. Am J Med Genet 149(A):1257–1262
Zon LI (2008) Intrinsic and extrinsic control of haematopoietic stem-cell self-renewal. Nature 453:306–313
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Honda, H. (2013). Hematopoietic Stem Cell Function and Skeletal Formation: Positive Role of Hemp Gene. In: Hayat, M. (eds) Stem Cells and Cancer Stem Cells, Volume 9. Stem Cells and Cancer Stem Cells, vol 9. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5645-8_15
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DOI: https://doi.org/10.1007/978-94-007-5645-8_15
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