• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. Feb 20, 1996; 93(4): 1677–1682.

An induction gene trap screen in embryonic stem cells: Identification of genes that respond to retinoic acid in vitro.


We have developed a novel induction gene trap approach that preselects in vitro for integrations into genes that lie downstream of receptor/ligand-mediated signaling pathways. Using this approach, we have identified 20 gene trap integrations in embryonic stem cells, 9 of which were induced and 11 of which were repressed after exposure to exogenous retinoic acid (RA). All but one of these integrations showed unique spatially restricted or tissue-specific patterns of expression between 8.5 and 11.5 days of embryogenesis. Interestingly, expression was observed in tissues that are affected by alterations in RA levels during embryogenesis. Sequence analysis of fusion transcripts from six integrations revealed five novel gene sequences and the previously identified protooncogene c-fyn. To date, germ-line transmission and breeding has uncovered one homozygous embryonic lethal and three homozygous viable insertions. These studies demonstrate the potential of this induction gene trap approach for identifying and mutating genes downstream of signal transduction pathways.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.7M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Joyner AL. Gene targeting and gene trap screens using embryonic stem cells: new approaches to mammalian development. Bioessays. 1991 Dec;13(12):649–656. [PubMed]
  • Hill DP, Wurst W. Gene and enhancer trapping: mutagenic strategies for developmental studies. Curr Top Dev Biol. 1993;28:181–206. [PubMed]
  • Skarnes WC, Auerbach BA, Joyner AL. 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 Dev. 1992 Jun;6(6):903–918. [PubMed]
  • Gossler A, Joyner AL, Rossant J, Skarnes WC. Mouse embryonic stem cells and reporter constructs to detect developmentally regulated genes. Science. 1989 Apr 28;244(4903):463–465. [PubMed]
  • Friedrich G, Soriano P. Promoter traps in embryonic stem cells: a genetic screen to identify and mutate developmental genes in mice. Genes Dev. 1991 Sep;5(9):1513–1523. [PubMed]
  • Wurst W, Rossant J, Prideaux V, Kownacka M, Joyner A, Hill DP, Guillemot F, Gasca S, Cado D, Auerbach A, et al. A large-scale gene-trap screen for insertional mutations in developmentally regulated genes in mice. Genetics. 1995 Feb;139(2):889–899. [PMC free article] [PubMed]
  • Linney E. Retinoic acid receptors: transcription factors modulating gene regulation, development, and differentiation. Curr Top Dev Biol. 1992;27:309–350. [PubMed]
  • Eichele G. Retinoids and vertebrate limb pattern formation. Trends Genet. 1989 Aug;5(8):246–251. [PubMed]
  • Simeone A, Acampora D, Arcioni L, Andrews PW, Boncinelli E, Mavilio F. Sequential activation of HOX2 homeobox genes by retinoic acid in human embryonal carcinoma cells. Nature. 1990 Aug 23;346(6286):763–766. [PubMed]
  • Simeone A, Acampora D, Nigro V, Faiella A, D'Esposito M, Stornaiuolo A, Mavilio F, Boncinelli E. Differential regulation by retinoic acid of the homeobox genes of the four HOX loci in human embryonal carcinoma cells. Mech Dev. 1991 Mar;33(3):215–227. [PubMed]
  • Pruitt SC. Expression of Pax-3- and neuroectoderm-inducing activities during differentiation of P19 embryonal carcinoma cells. Development. 1992 Nov;116(3):573–583. [PubMed]
  • Conlon RA, Rossant J. Exogenous retinoic acid rapidly induces anterior ectopic expression of murine Hox-2 genes in vivo. Development. 1992 Oct;116(2):357–368. [PubMed]
  • Marshall H, Nonchev S, Sham MH, Muchamore I, Lumsden A, Krumlauf R. Retinoic acid alters hindbrain Hox code and induces transformation of rhombomeres 2/3 into a 4/5 identity. Nature. 1992 Dec 24;360(6406):737–741. [PubMed]
  • Hill DP, Wurst W. Screening for novel pattern formation genes using gene trap approaches. Methods Enzymol. 1993;225:664–681. [PubMed]
  • Nagy A, Rossant J, Nagy R, Abramow-Newerly W, Roder JC. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8424–8428. [PMC free article] [PubMed]
  • Eustice DC, Feldman PA, Colberg-Poley AM, Buckery RM, Neubauer RH. A sensitive method for the detection of beta-galactosidase in transfected mammalian cells. Biotechniques. 1991 Dec;11(6):739–743. [PubMed]
  • Cooke MP, Perlmutter RM. Expression of a novel form of the fyn proto-oncogene in hematopoietic cells. New Biol. 1989 Oct;1(1):66–74. [PubMed]
  • Stein PL, Lee HM, Rich S, Soriano P. pp59fyn mutant mice display differential signaling in thymocytes and peripheral T cells. Cell. 1992 Sep 4;70(5):741–750. [PubMed]
  • Vasios G, Mader S, Gold JD, Leid M, Lutz Y, Gaub MP, Chambon P, Gudas L. The late retinoic acid induction of laminin B1 gene transcription involves RAR binding to the responsive element. EMBO J. 1991 May;10(5):1149–1158. [PMC free article] [PubMed]
  • Kessel M, Gruss P. Homeotic transformations of murine vertebrae and concomitant alteration of Hox codes induced by retinoic acid. Cell. 1991 Oct 4;67(1):89–104. [PubMed]
  • Langston AW, Gudas LJ. Identification of a retinoic acid responsive enhancer 3' of the murine homeobox gene Hox-1.6. Mech Dev. 1992 Sep;38(3):217–227. [PubMed]
  • Pöpperl H, Featherstone MS. Identification of a retinoic acid response element upstream of the murine Hox-4.2 gene. Mol Cell Biol. 1993 Jan;13(1):257–265. [PMC free article] [PubMed]
  • Lohnes D, Kastner P, Dierich A, Mark M, LeMeur M, Chambon P. Function of retinoic acid receptor gamma in the mouse. Cell. 1993 May 21;73(4):643–658. [PubMed]
  • Sucov HM, Dyson E, Gumeringer CL, Price J, Chien KR, Evans RM. RXR alpha mutant mice establish a genetic basis for vitamin A signaling in heart morphogenesis. Genes Dev. 1994 May 1;8(9):1007–1018. [PubMed]
  • Yagi T, Shigetani Y, Furuta Y, Nada S, Okado N, Ikawa Y, Aizawa S. Fyn expression during early neurogenesis in mouse embryos. Oncogene. 1994 Sep;9(9):2433–2440. [PubMed]
  • Stein PL, Lee HM, Rich S, Soriano P. pp59fyn mutant mice display differential signaling in thymocytes and peripheral T cells. Cell. 1992 Sep 4;70(5):741–750. [PubMed]
  • Gossen M, Bujard H. Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5547–5551. [PMC free article] [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...