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Titolo:
Bidirectional transcriptional activity of PGK-neomycin and unexpected embryonic lethality in heterozygote chimeric knockout mice
Autore:
Scacheri, PC; Crabtree, JS; Novotny, EA; Garrett-Beal, L; Chen, A; Edgemon, KA; Marx, SJ; Spiegel, AM; Chandrasekharappa, SC; Collins, FS;
Indirizzi:
NHGRI, NIH, Bethesda, MD 20892 USA NHGRI Bethesda MD USA 20892NHGRI, NIH, Bethesda, MD 20892 USA NIDDKD, Bethesda, MD 20892 USA NIDDKD Bethesda MD USA 20892NIDDKD, Bethesda, MD 20892 USA
Titolo Testata:
GENESIS
fascicolo: 4, volume: 30, anno: 2001,
pagine: 259 - 263
SICI:
1526-954X(200108)30:4<259:BTAOPA>2.0.ZU;2-J
Fonte:
ISI
Lingua:
ENG
Soggetto:
MEN1 GENE; EXPRESSION; LOCUS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
9
Recensione:
Indirizzi per estratti:
Indirizzo: Collins, FS NHGRI, NIH, Bldg 31,Room 4B09,31 Ctr Dr, Bethesda, MD 20892 USA NHGRI Bldg 31,Room 4B09,31 Ctr Dr Bethesda MD USA 20892 92 USA
Citazione:
P.C. Scacheri et al., "Bidirectional transcriptional activity of PGK-neomycin and unexpected embryonic lethality in heterozygote chimeric knockout mice", GENESIS, 30(4), 2001, pp. 259-263

Abstract

In an effort to create a conventional knockout mouse model for multiple endocrine neoplasia type 1 (MEN1), we targeted disruption of the mouse Men I gene through homologous recombination in ES cells. Men1 exons 2-4 were replaced by a PGK-neomycin cassette inserted in the opposite direction of Men1 transcription (Men1(MSK/+)). Unexpectedly, the Men1 conventional knockout was lethal in heterozygous, chimeric animals. Analysis of embryos revealed late gestational lethality with some embryos showing omphalocele. This was avery surprising phenotype, given that humans and mice that are heterozygotes for loss of function mutations in MEN1 are phenotypically normal except for a risk of endocrine tumors. Northern analysis of Men1(MSK/+) embryonic stem cell RNA revealed the presence of an abundant, novel transcript of 2.1kb, in addition to the expected wild-type transcripts of 2.7 kb and 3.1 kb. RT-PCR analysis identified this aberrant transcript as arising from the antisense strand of the PGK promoter. We hypothesize that this transcript isproducing either a toxic effect at the RNA level, or a dominant negative effect through the production of an amino-terminal truncated protein product. This example serves as a cautionary reminder that mouse knockouts using PGK-neo may sometimes display phenotypes that reflect more than just the loss of function of the targeted gene. Published 2001 Wiley-Liss, Inc.(dagger)

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 01/04/20 alle ore 11:26:00