Skip Navigation

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (25)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Smith, D. J.
Right arrow Articles by Rubin, E. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Smith, D. J.
Right arrow Articles by Rubin, E. M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Human Molecular Genetics Pages 1729-1734  
Functional screening and complex traits: human 21q22.2 sequences affecting learning in mice
Introduction
An Increased Dose Of 21q22.2 Gives Defined Phenotypes
Behavioral Analysis Of The In Vivo Library
Neuroanatomical And Neurophysiological Analysis Of The In Vivo Library
Localizing A Gene Involved In Learning And Memory
Dyrk Is Responsible For The Learning And Memory Deficits
Conclusions
References

Functional screening and complex traits: human 21q22.2 sequences affecting learning in mice

Functional screening and complex traits: human 21q22.2 sequences affecting learning in mice

Desmond J. Smith*, Edward M. Rubin

Human Genome Center, Lawrence Berkeley National Laboratory, Building 74, 1 Cyclotron Road, Berkeley, CA 94720, USA

Received May 2, 1997

Libraries of the mammalian genome have generally been propagated in single cells and have been used for gene discovery through in vitro analyses. We have expanded upon this concept by the creation of panels of YAC transgenic mice propagating targeted megabase regions of the genome. Such a panel of mice can be called an `in vivo library' and genes can be identified based on functional screens of members of the library. To test this approach, we created a 2 Mb in vivo library of human chromosome 21q22.2. Analysis of the library has revealed that one 570 kb YAC, in two separate founder lines, was associated with distinct learning deficits compared with the other 21q22 YAC transgenics and non-transgenic control animals. We have localized the gene on the YAC that causes the deficits by taking advantage of fragmentation of the YAC during the process of microinjection. The responsible gene is the human minibrain gene, and the homolog of the gene in Drosophila is also associated with learning defects. These results suggest that altered dosage of minibrain is associated with abnormal neural development in flies and mice and, in humans, may also be involved in the molecular pathology of Down syndrome.

INTRODUCTION

The clear challenge facing the post-genome world is the task of `functional genomics', interpreted here as understanding how the genes discovered from DNA sequencing function in the living organism. This challenge has already given rise to ingenious innovations focusing on how arrays of genes interact to control each other at the level of transcription (1,2) or at the protein-protein level (3,4). With regard to studies of mammals, however, fewer studies have concentrated on the level of the whole organism. The advantage of investigations on the intact animal is that information obtained about the function of genes in the setting of the whole organism is often unobtainable by other approaches.

Approaches which have provided information on gene function in the mouse include gene targeting and transgenesis of single genes. Although insightful, these approaches suffer from low throughput. Recent technical innovations in large insert transgenesis (5-12) and in creation of large deletions (13,14) have increased the number of genes that can be examined at once in a single animal and have increased the potential throughput of performing genotype/phenotype analysis in the mouse. The work described here concentrates on the approach in which large segments of DNA are added to the genome of the host organism.

To examine genotype/phenotype in a candidate region of the genome, panels of mice containing large inserts from this region are created (15,16). These panels of transgenic mice containing large pieces of DNA from the human genome are referred to as in vivo libraries (15) (Fig. 1). Libraries, of all or part of an organism's genome, have been very important in the history of molecular biology. Traditionally, they have been propagated in prokaryotes, lower eukaryotes (yeast) or occasionally in somatic eukaryotic cells. In the approach described here, a targeted segment of the human genome is propagated in a eukaryotic metazoan host, the mouse. The advantage of this approach is that unique information is obtained about the function of genes in the library in the context of a higher eukaryote, the mouse, outweighing many of the disadvantages inherent in studies of this low throughput organism. A detailed discussion of other approaches is given in Kola and Hertzog in this issue (17).

AN INCREASED DOSE OF 21q22.2 GIVES DEFINED PHENOTYPES

As an initial foray into the use of in vivo libraries, we have concentrated on a 2 Mb region on the long arm of human chromosome 21 at 21q22.2. There is evidence, albeit controversial, that an extra copy of this segment of chromosome 21 is sufficient to cause many of the phenotypic features of Down syndrome (18). In addition, mouse models of Down syndrome have been created using classical genetics (19,20). One of the models consists of animals with an extra dose of the region of mouse chromosome 16 syntenic with human chromosome 21 (20). These animals display a number of phenotypes, including deficits in learning and memory. Hence, 21q22.2 was a particularly attractive region of the genome, because the phenotypes displayed by Down syndrome individuals and the mouse models provided a good prototype for the kinds of phenotypes to be expected from the in vivo library. Furthermore, since Down syndrome is associated with a sizable constellation of phenotypes, which are most likely due in different measure to distinct genes, the syndrome can properly be regarded as a complex trait.


Figure 1 In vivo library of a defined segment of the genome in transgenic mice.


Figure 2 The YACs used in the creation of the transgenic mice. (A) Molecular map of the 21q22.2 YACs employed in the creation of the panel of transgenic mice. (B) The 152F7 YAC fragments as judged by STS content mapping. The human minibrain gene and its direction of transcription is also shown. The intron/exon structure of the human minibrain gene is highly conserved with the Drosophila gene. In addition to the two independent lines of mice containing the full length unrearranged YAC 152F7, a number of lines of mice were obtained containing fragments of the YAC, and these fragments are depicted below the diagram of the minibrain gene. The 180 kb telomeric fragment of 152F7 is shown as 152F7 tel, whereas the complementary 390 kb centromeric fragment is shown as 152F7 cen.

An in vivo library of this 2 Mb region of the human genome was created using four YACs spanning the region of interest (15) (Figs. 1,1). The library spans 4% of human chromosome 21. The integrity of the YAC transgenes in the mouse genome was established by inter-alu PCR fingerprinting (15). The copy number of the YAC transgenes was assessed, and their integrity further confirmed, by FISH (16). This analysis showed that the copy number of the YAC transgenes ranged from 1 to 3 copies per mouse genome, and suggested that there was low level overexpression of the genes present on the YACs. Furthermore, RT-PCR analysis of at least one transcription unit on each one of the YACs suggested that the human genes were correctly transcribed in the foreign environment of the mouse genome (15). For each YAC, two or more independent lines of animals containing the full length transgene were created, in order to be certain that any phenotypes observed in members of the library were replicated by the two independent lines. In this way, it could be verified that any phenotypes observed were most likely due to the extra copy of genetic information provided by the transgene, and not simply due to insertion effects of the transgene inserting into an endogenous mouse gene.

BEHAVIORAL ANALYSIS OF THE IN VIVO LIBRARY

Because the spectrum of genes involved in learning and memory are still largely unknown, and the deficits in these processes are amongst the most important practical consequences of Down syndrome, the learning and memory of the 21q22.2 in vivo library was investigated (16). The Morris water maze, which has become a widely accepted test of learning and memory for small rodents, was employed. In comparison with non-transgenic controls, the most severe deficits on this test were shown by animals containing YAC 152F7, while milder deficits were shown by animals containing YAC 230E8 (Fig. 2). No deficits were shown by animals containing the other two YACs, compared with the control animals.


Figure 3 The Morris reverse probe test (crossings). The ability of the mice to learn and remember the position of a hidden platform in a swimming pool is quantitated by their persistence in searching the section of the pool (red) in which the platform is located. The non-transgenic controls search this quadrant significantly more vigorously than animals containing YAC 152F7, which show no evidence of learning on this phase of the test. Animals containing YAC 230E8 show an intermediate level of performance (not shown).

NEUROANATOMICAL AND NEUROPHYSIOLOGICAL ANALYSIS OF THE IN VIVO LIBRARY

Hippocampal long-term potentiation has been proposed as an in vitro electrophysiological correlate of learning and memory. Based on this, we investigated hippocampal long-term potentiation in the brains of mice belonging to the in vivo library. No abnormalities were shown by any of the groups of animals, suggesting that if an electrophysiological defect does exist, it may reside in a region of the brain other than the hippocampus. The lack of electrophysiological defects observed in any members of the library prompted an analysis of the neuroanatomic pathology of the library. Interestingly, this revealed that animals containing YAC 230E8, which displayed the mild defects in learning and memory, showed a significantly increased density of neurons in the cerebral cortex. This abnormal density of neurons may explain the learning and memory deficits of these animals. Both learning deficits (21,22) and cognitive abnormalities (23) have been linked with increased neuronal density. The increased density may cause these defects by interfering with neuronal signalling. However, since Down syndrome may be regarded as a complex trait, the ultimate phenotypes of the syndrome could represent the epistatic and synergistic effects of many genes interacting together. Investigating the effects on cortical neuronal density of combinations of different YACs from 21q22.2 in the same mice may therefore be illuminating.

LOCALIZING A GENE INVOLVED IN LEARNING AND MEMORY

To localize the gene responsible for the learning and memory deficits of mice containing YAC 152F7, advantage was taken of the observation that fragmentation of the lengthy YAC DNA occurs during handling for microinjection. This leads to a panel of animals that contains random fragments of the YAC, in addition to animals containing the full length unrearranged YAC (Fig. 1). The animals containing random YAC fragments provide a valuable resource for ultra-fine structure mapping of genetic traits, since the number of break points obtainable as a result of the fragmentation are far more numerous than one can practicably obtain using classical meiotic genetic mapping. Of the animals containing random fragments of YAC 152F7, animals containing a 180 kb telomeric fragment of the YAC showed learning and memory deficits that were indistinguishable from animals containing the full length YAC, whereas animals containing a complementary 390 kb centromeric fragment showed normal learning and memory. The fragmented YAC studies had thus reduced the interval containing the sequence(s) contributing to the learning defects from 570 to 180 kb.

DYRK IS RESPONSIBLE FOR THE LEARNING AND MEMORY DEFICITS

The only gene that appears to be present in the 180 kb telomeric region (24) is DYRK (16,25-32). Expression studies confirmed that this gene was overexpressed as a result of the transgenesis with both the full length YAC 152F7 and the telomeric fragment, and that the level of overexpression was consistent with the copy number of the transgenes.

The DYRK gene is >100 kb and is the human homolog of the Drosophila gene minibrain (32). Hypomorphic alleles of minibrain in the fruitfly give rise to defects in learning and memory, together with decreased brain weight and decreased numbers of neurons. The gene is a dual specificity tyrosine/serine-threonine protein kinase related to genes involved in cell cycle control (27). minibrain is expressed in developing neuroblasts in Drosophila (32), and is expressed ubiquitously in mice, but most strongly in the brain, especially in the cerebral cortex, cerebellum, hippocampus and the olfactory lobes (26,30,31). Thus, the work described here, together with the Drosophila work, suggests that correct dosage of the minibrain gene is crucial for normal development of the nervous system.

CONCLUSIONS

By using an in vivo library of large insert transgenic animals containing DNA from human chromosome 21q22.2, together with a functional assay, we have demonstrated that it is possible to sift through a large genomic region and identify distinct sequences affecting learning. Our findings that two different YAC transgenes cause distinct learning defects are consistent with studies in humans suggesting that several different loci may contribute to the learning deficits resulting from an extra chromosome 21 (33). In addition, the analysis of the in vivo library enabled the identification of a human gene (DYRK) from 21q22.2 causing learning defects in mice, the homolog of which (minibrain) had previously been shown to be involved in learning and memory in Drosophila. Together, these observations suggest that the human gene may contribute to the learning deficits of Down syndrome. Other demonstrations of the utility of in vivo libraries include the biological annotation of genomic sequence data (34), and the fine mapping of the mouse neurological mutation vibrator by in vivo complementation, leading to the successful identification of the gene (35).

As the sequencing of the human genome begins in earnest, it is clear that the task that will confront us is to understand how networks of genes contribute to development and physiology in health and disease. This is exemplified by the contemporary interest in complex trait analysis, both for its basic theoretical interest and practical ramifications (36,37). However, the identification of genes involved in human complex traits has been difficult because of genetic heterogeneity and because many genes, each individually with low impact, can conspire together with environment to give rise to the eventual phenotype of interest. The use of in vivo libraries of large insert transgenic mice offers an approach to examine a large region of genomic DNA that may be defined by complex trait analysis. Since the transgenic animals harbor many genes it is possible to investigate the effects of many genes upon one biological phenotype at once, and the approach can hence be effectively regarded as a method to perform multiplex analysis of the relationship between genotype and phenotype. Analysis of the phenotypes displayed by library members, based upon functional data, could be used to define candidate genes for further analysis in human populations enabling association rather than linkage studies (38) to be employed in the identification of genes contributing to complex traits.

REFERENCES

1. Schena, M., Shalon, D., Davis, R.W. and Brown, P.O. (1995) Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science 270, 467-470. MEDLINE Abstract

2. Wang, M.X. and Church, G.M. (1992) A whole genome approach to in vivo DNA-protein interactions in E. coli. Nature 360, 606-610. MEDLINE Abstract

3. Bartel, P.L., Roecklein, J.A., SenGupta, D. and Fields, S. (1996) A protein linkage map of Escherichia coli bacteriophage T7. Nature Genet. 12, 72-77. MEDLINE Abstract

4. Mendelsohn, A.R. and Brent, R. (1994) Applications of interaction traps/two-hybrid systems to biotechnology research. Curr. Opin. Biotech. 5, 482-486.

5. Jakobovits, A., Moore, A.L., Green, L.L., Vergara, G.J., Maynard-Currie, C.E., Austin, H.A. and Klapholz, S. (1993) Germ-line transmission and expression of a human-derived yeast artificial chromosome. Nature 362, 255-258. MEDLINE Abstract

6. Lamb, B.T., Sisodia, S.S., Lawler, A.M., Slunt, H.H., Kitt, C.A., Kearns, W.G., Pearson, P.L., Price, D.L. and Gearhart, J.D. (1993) Introduction and expression of the 400 kilobase precursor amyloid protein gene in transgenic mice. Nature Genet. 5, 22-30. MEDLINE Abstract

7. Peterson, K.R., Clegg, C.H., Huxley, C., Josephson, B.M., Haugen, H.S., Furukawa, T. and Stamatoyannopoulos, G. (1993) Transgenic mice containing a 248-kb yeast artificial chromosome carrying the human [beta]-globin locus display proper developmental control of human globin genes. Proc. Natl. Acad. Sci. USA 90, 7593-7597.

8. Schedl, A., Montoliu, L., Kelsey, G. and Schütz, G. (1993) A yeast artificial chromosome covering the tyrosinase gene confers copy number-dependent expression in transgenic mice. Nature 362, 258-261. MEDLINE Abstract

9. Strauss, W.M., Dausman, J., Beard, C., Johnson, C., Lawrence, J.B. and Jaenisch, R. (1993) Germ line transmission of a yeast artificial chromosome spanning the murine [alpha]1(I) collagen locus. Science 259, 1904-1907. MEDLINE Abstract

10. Frazer, K.A., Narla, G., Zhang, J.-L. and Rubin, E.M. (1995) The apolipoprotein(a) gene is regulated by sex hormones and acute-phase inducers in YAC transgenic mice. Nature Genet. 9, 424-431. MEDLINE Abstract

11. Linton, M.F., Farese, R.V., Jr., Chiesa, G., Grass, D.S., Chin, P., Hammer, R.E., Hobbs, H.H. and Young, S.G. (1993) Transgenic mice expressing high plasma concentrations of human apolipoprotein B100 and lipoprotein(a). J. Clin. Invest. 92, 3029-3037.

12. Callow, M.J., Stoltzfus, L.J., Lawn, R.M. and Rubin, E.M. (1994) Expression of human apolipoprotein B and assembly of lipoprotein(a) in transgenic mice. Proc. Natl. Acad. Sci. USA 91, 2130-2134.

13. Ramirez-Solis, R., Liu, P. and Bradley, A. (1995) Chromosome engineering in mice. Nature 378, 720-724. MEDLINE Abstract

14. You, Y., Bergstrom, R., Klemm, M., Lederman, B. et al.) (1997) Chromosomal deletion complexes in mice by radiation of embryonic stem cells. Nature Genet. 15, 285-288. MEDLINE Abstract

15. Smith, D.J., Zhu, Y., Zhang, J.-L., Cheng, J.-F. and Rubin, E.M. (1995) Construction of a panel of transgenic mice containing a contiguous 2-Mb set of YAC/P1 clones from human chromosome 21q22.2. Genomics 27, 425-434. MEDLINE Abstract

16. Smith, D.J., Stevens, M.E., Sudanagunta, S.P., Bronson, R.T., Makhinson, M., Watabe, A.M., O'Dell, T.J., Fung, J., Weier, H.-U.G., Cheng, J.-F. and Rubin, E.M. (1997) Functional screening of 2 Mb of human 21q22.2 in transgenic mice implicates minibrain in the learning defects associated with Down syndrome. Nature Genet. 16, 28-36. MEDLINE Abstract

17. Kola, I., and Hertzog, P.J. (1997) Animal models in the study of the biological function of genes on chromosome 21 and their role in the pathophysiology of Down syndrome. Hum. Mol. Genet. 6, 1713-1727.

18. Rahmani, Z., Blouin, J.-L., Creau-Goldberg, N., Watkins, P.C., Mattei, J.-F., Poissonnier, M., Prieur, M., Chettouh, Z., Nicole, A., Aurias, A., Sinet, P.-M. and Delabar, J.-M. (1989) Critical role of the D21S55 region on chromosome 21 in the pathogenesis of Down syndrome. Proc. Natl. Acad. Sci. USA 86, 5958-5962.

19. Cox, D.R., Smith, S.A., Epstein, L.B. and Epstein, C.J. (1984) Mouse trisomy 16 as an animal model of human trisomy 21 (Down syndrome): production of viable trisomy 16 diploid mouse chimeras. Develop. Biol. 101, 416-424. MEDLINE Abstract

20. Reeves, R.H., Irving, N.G., Moran, T.H., Wohn, A., Kitt, C., Sisodia, S.S., Schmidt, C., Bronson, R.T. and Davisson, M.T. (1995) A mouse model for Down syndrome exhibits learning and behaviour defecits. Nature Genet. 11, 177-184. MEDLINE Abstract

21. Bauman, M.L., Kemper, T.L. and Arin, D.M. (1995) Pervasive neuroanatomic abnormalities of the brain in three cases of Rett's syndrome. Neurology 45, 1581-1586. MEDLINE Abstract

22. Johnston, M.V., Hohmann, C. and Blue, M.E. (1995) Neurobiology of Rett syndrome. Neuropediatrics 26, 119-122. MEDLINE Abstract

23. Selemon, L.D., Rajkowska, G. and Goldman-Rakic, P.S. (1995) Abnormally high neuronal density in the schizophrenic cortex. A morphometric analysis of prefrontal area 9 and occipital area 17. Arch. Gen. Psychiatry 52, 805-820.

24. Ohira, M., Seki, N., Nagase, T., Suzuki, E. et al). (1997) Gene identification in 1.6-Mb region of the Down syndrome region on chromosome 21. Genome Res. 7, 47-58. MEDLINE Abstract

25. Cheng, J.-F., Boyartchuk, V. and Zhu, Y. (1994) Isolation and mapping of human chromosome 21 cDNA: progress in constructing a chromosome 21 expression map. Genomics 23, 75-84.

26. Guirema, J., Casas, C., Pucharcos, C., Solans, A., Domenech, A., Planas, A.M., Ashley, J., Lovett, M., Estivill, X. and Pritchard, M.A. (1996) A human homologue of Drosophila minibrain (MNB) is expressed in the neuronal regions affected in Down syndrome and maps to the critical region. Hum. Mol. Genet. 5, 1305-1310.

27. Kentrup, H., Becker, W., Heukelbach, J., Wilmes, A., Schurmann, A., Huppertz, C., Kainulainen, H. and Joost, H.-G. (1996) Dyrk, a dual specificity protein kinase with unique strucutural features whose activity is dependent on tyrosine residues between subdomains VII and VIII. J. Biol. Chem. 271, 3488-3495.

28. Patil, N., Cox, D.R., Bhat, D., Faham, M., Myers, R.M. and Peterson, A.S. (1995) A potassium channel mutation in weaver mice implicates membrane excitability in granule cell differentiation. Nature Genet. 11, 126-129. MEDLINE Abstract

29. Peterson, A., Patil, N., Robbins, C., Wang, L., Cox, D.R. and Myers, R.M. (1994) A transcript map of the Down syndrome critical region on chromosome 21. Hum. Mol. Genet. 3, 1735-1742.

30. Shindoh, N., Kudoh, J., Maeda, H., Yamaki, A., Minoshima, S., Shimizu, Y. and Shimizu, N. (1996) Cloning of a human homolog of the Drosophila Minibrain/Rat Dyrk gene from `the Down syndrome critical region' of chromosome 21. Biochem. Biophys. Res. Comm. 225, 92-99. MEDLINE Abstract

31. Song, W.-J., Sternberg, L.R., Kasten-Sportes, C., Van Keuren, M.L., Chung, S.-H., Slack, A.C., Miller, D.E., Glover, T.W., Chiang, P.-W., Lou, L. and Kurnit, D.M. (1996) Isolation of human and murine homologues of the Drosophila minibrain gene: human homologue maps to 21q22.2 in the Down syndrome `critical region'. Genomics 38, 331-339.

32. Tejedor, F., Zhu, X.R., Kaltenbach, E., Ackermann, A., Baumann, A., Canal, I., Heisenberg, M., Fischbach, K.F. and Pongs, O. (1995) minibrain: a new protein kinase family involved in postembryonic neurogenesis in Drosphila. Neuron 14, 287-301. MEDLINE Abstract

33. Korenberg, J.R., Chen, X.-N., Schipper, R., Sun, Z., Gonsky, R., Gerwehr, S., Carpenter, N., Daumer, C., Dignan, P., Disteche, C., Graham, J.M., Hugdins, L., McGillivray, B., Miyazaki, K., Ogasawara, N., Park, J.P., Pagon, R., Pueschel, S., Sack, G., Say, B., Schuffenhauer, S., Soukup, S. and Yamanaka, T. (1994) Down syndrome phenotypes: the consequences of chromosomal imbalance. Proc. Natl. Acad. Sci. USA 91, 4997-5001.

34. Frazer, K.A., Ueda, Y., Zhu, Y., Gifford, V.R., Garafolo, M., Mohandas, N., Martin, C.H., Palazzolo, M.J., Cheng, J.-F. and Rubin, E.M. (1997) Computational and biological analysis of 680 kilobases of DNA sequence from the human 5q31 cytokine gene cluster region. Genome Res. 7, 495-512. MEDLINE Abstract

35. Hamilton, B.A., Smith, D.J., Mueller, K.L., Kerrebrock, A.W., Bronson, R.T., van Berkel, V., Daly, M.J., Kruglyak, L., Reeve, M.P., Nemhauser, J.L., Hawkins, T.L., Rubin, E.M. and Lander, E.S. (1997) The vibrator mutation causes neurodegeneration via reduced expression of PITP[alpha]: positional complementation cloning and extragenic suppression. Neuron 18, 711-722. MEDLINE Abstract

36. Lander, E.S. and Schork, N.J. (1994) Genetic dissection of complex traits. Science 265, 2037-2048. MEDLINE Abstract

37. Vyse, T.J. and Todd, J.A. (1996) Genetic analysis of autoimmune disease. Cell 85, 311-318. MEDLINE Abstract

38. Risch, N. and Merikangas, K. (1996) The future of genetic studies of complex human diseases. Science 273, 1516-1517. MEDLINE Abstract

*To whom correspondence should be addressed. Tel: +1 510 486 5468; Fax: +1 510 486 6746; Email: des@ux5.lbl.gov

-->
This page is maintained by OUP admin. Last updated Fri Sep 12 18:09:23 BST 1997. Part of the OUP Journals World Wide Web service. Copyright Oxford University Press, 1997


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Physiol. GenomicsHome page
J. M. Lignon, Z. Bichler, B. Hivert, F. E. Gannier, P. Cosnay, J. A. del Rio, D. Migliore-Samour, and C. O. Malecot
Altered heart rate control in transgenic mice carrying the KCNJ6 gene of the human chromosome 21
Physiol Genomics, April 1, 2008; 33(2): 230 - 239.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Biol. CellHome page
P. A. Kelly and Z. Rahmani
DYRK1A Enhances the Mitogen-activated Protein Kinase Cascade in PC12 Cells by Forming a Complex with Ras, B-Raf, and MEK1
Mol. Biol. Cell, August 1, 2005; 16(8): 3562 - 3573.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
J. H. Sitz, M. Tigges, K. Baumgartel, L. G. Khaspekov, and B. Lutz
Dyrk1A Potentiates Steroid Hormone-Induced Transcription via the Chromatin Remodeling Factor Arip4
Mol. Cell. Biol., July 1, 2004; 24(13): 5821 - 5834.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
V. Rochat-Steiner, K. Becker, O. Micheau, P. Schneider, K. Burns, and J. Tschopp
Fist/Hipk3: A FAS/Fadd-Interacting Serine/Threonine Kinase That Induces Fadd Phosphorylation and Inhibits FAS-Mediated Jun Nh2-Terminal Kinase Activation
J. Exp. Med., October 16, 2000; 192(8): 1165 - 1174.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
M. J. Justice, JaniceK. Noveroske, JohnS. Weber, B. Zheng, and A. Bradley
Mouse ENU Mutagenesis
Hum. Mol. Genet., September 1, 1999; 8(10): 1955 - 1963.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. van Es, K. E. Weening, and P. N. Devreotes
The Protein Kinase YakA Regulates G-protein-linked Signaling Responses during Growth and Development of Dictyostelium
J. Biol. Chem., August 10, 2001; 276(33): 30761 - 30765.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (25)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Smith, D. J.
Right arrow Articles by Rubin, E. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Smith, D. J.
Right arrow Articles by Rubin, E. M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?