Sci. Aging Knowl. Environ., 18 August 2004
Vol. 2004, Issue 33, p. tg4
GENETICALLY ALTERED MICE
||Rtel (Regulator of telomere length) gene
|Type of change
||Targeted disruption of the gene in R1 embryonic stem (ES) cells, resulting in the replacement of exons 7 to 9 with a heterologous sequence to produce a null allele.
|Nature of protein
||The Rtel locus encodes a helicase-like protein that might be required for the resolution of higher-order structures of guanine (G)-rich DNA. G-rich telomeric repeats are expected to be prone to the formation of such higher-order structures; in general, these structures might arise during replication, repair, recombination, or transcription of G-rich DNA.
||Rtel/ mice die by embryonic stage E11.5. Before death, they exhibit defects in the development of tissues that display rapid cell proliferation, including the nervous system, heart, vasculature, and extraembryonic tissues.
Rtel/ embryos display subcutaneous hematomas throughout the body and limbs, suggesting defective circulation as an underlying factor in the retarded growth and developmental phenotypes. The placenta of Rtel/ mutants was also found to exhibit attenuated fetal blood vessel formation, implying that poor embryonic viability was associated with defective differentiation of the extraembryonic trophectoderm, which ultimately forms the placenta.
|Corresponding human phenotype
||Unknown; the human homolog novel helicase-like (NHL) gene has been mapped to chromosomal region 20q13.3.
||H. Ding, M. Schertzer, X. Wu, M. Gertsenstein, S. Selig, M. Kammori, R. Pourvali, S. Poon, I. Vulto, E. Chavez, P. P. L. Tam, A. Nagy, P. Lansdorp, Regulation of murine telomere length by Rtel: An essential gene encoding a helicase-like protein. Cell 117, 873-886 (2004).
||Authors of primary reference.
||Rtel/ ES cells display significant telomere loss. Additionally, numerous chromosome breaks and fusions are observed if ES cell differentiation is induced in vitro.
Telomere length was examined in the offspring of a cross between an Rtel+/ heterozygote (Mus musculus) with an interfertile species of mice, M. spretus, which has substantially shorter telomeres than does M. musculus. If the Rtel null allele was inherited by the offspring, the telomere length of the M. spretus-derived chromosomes remained short; if the wild-type Rtel allele was inherited from the M. musculus parent, the telomere length of the M. spretus-derived chromosomes was increased. Thus, the wild-type M. musculus Rtel allele is required for the elongation of M. spretus telomeres.
Additional clues to the function of the Rtel gene product come from the analysis of a Caenorhabditis elegans dog-1 mutant, which exhibits deletions of G-rich DNA. The dog-1 gene encodes a product with sequence similarity to the Rtel product and is hypothesized to function in the resolution of higher-order structures that form in G-rich DNA.
||Related transgenic/knockout mice:
Werner mouse K577M-WRN http://sageke.sciencemag.org/cgi/content/full/sageke;2002/13/tg2
Werner mouse Wrn-null http://sageke.sciencemag.org/cgi/content/full/sageke;2002/13/tg3
Werner mouse Wrn-hel http://sageke.sciencemag.org/cgi/content/full/sageke;2002/13/tg4
||regulation of telomere length
August 18, 2004
- C. Bai, B. Connolly, M. L. Metzker, C. A. Hilliard, X. Liu, V. Sandig, A. Soderman, S. M. Galloway, Q. Liu, C. P. Austin, C. T. Caskey. Overexpression of M68/DcR3 in human gastrointestinal tract tumors independent of gene amplification and its location in a four-gene cluster. Proc. Natl. Acad. Sci. U.S.A. 97, 1230-1235 (2000).[Abstract/Free Full Text]
- I. Cheung, M. Schertzer, A. Rose, P. M. Lansdorp, Disruption of dog-1 in Caenorhabditis elegans triggers deletions upstream of guanine-rich DNA. Nat. Genet. 31, 405-409 (2002).[Medline]
- H. Ding, M. Schertzer, X. Wu, M. Gertsenstein, S. Selig, M. Kammori, R. Pourvali, S. Poon, I. Vulto, E. Chavez, P. P. L. Tam, A. Nagy, P. Lansdorp, Regulation of murine telomere length by Rtel: An essential gene encoding a helicase-like protein. Cell 117, 873-886 (2004).[CrossRef][Medline]
- L. Zhu, K. S. Hathcock, P. Hande, P. M. Lansdorp, M. F. Seldin, R. J. Hodes, Telomere length regulation in mice is linked to a novel chromosome locus. Proc. Natl. Acad. Sci. U.S.A. 95, 8648-8653 (1998).[Abstract/Free Full Text]
Mice. Sci. Aging Knowl. Environ. 2004
(33), tg4 (2004).