|Title:||Ashbel Smith Professor Emeritus|
|Education:||Ph.D.: 1972, Cornell University Medical School, Graduate School of Medicine; B.A.: 1964, Cornell University|
|Postdoc.:||Pasteur Institut, Paris, France|
|Research:||Mammalian developmental genetics|
|Artzt Laboratory home page:http://web.biosci.utexas.edu/artzt_lab/|
The T/t complex in the mouse provides material that is potentially very important for studying early mammalian development. It can be defined as a variant region of chromosome 17 that spans the proximal part of the chromosome. Historically, the T/t region has been intensively investigated because, until a few years ago when “knock out” technology became available, the majority of developmental lethal mutations known in mammals resided in the T/t complex. This was because the region contains a natural reporter system for embryonic lethals. The biology and phenotypes of over 25 mutations have been well characterized and they are all known to have varied but essential functions in early mouse development.
My lab has concentrated on positionally cloning and analyzing these mutations. We have been successful with two; one of which, quaking, has revealed what may be a new cellular pathway. quaking (qk) is a pleiotropic gene essential for myelination of the nervous system and also critical for development at mid-gestation. The cloning of qk has uncovered an ancient gene family conserved from yeast to man. It is a new sub-family of KH domain-containing, RNA-binding proteins called ‘maxi’ KH. Mutations with interesting developmental phenotypes have been identified in C. elegans, Drosophila and mouse. Members of this family include qk in mouse and Drosophila, the germline line deficient-1 (gld-1) mutation from C. elegans and the most studied member, mammalian Sam68. The latter not only binds RNA, but is a central player in signal transduction as a downstream target src and fyn as well as binding the adapter proteins Grb2 and Nck. The pathway this family defines has been nick-named STAR for signal transduction and activation of RNA. We are presently involved in cloning the other family members and analyzing their functional role in RNA metabolism most probably in the regulation of alternate splicing and also cell signaling. The data suggest a new information pathway in cells undergoing a final developmental transition.
Brachyury (T) is a semidominant gene residing in the t-complex. In association with the t complex tail factor (tct) of t haplotypes, it has been proposed as an important model of spina bifida. T has been cloned and shown to be a useful marker for the genesis of axial mesoderm. It encodes a novel family of transcription factors know as T-box genes. We have used a transgenic insertion mutation to define a long-postulated second Brachyury gene named “Brachyury the second” (T2) 25 kb upstream of the first T gene. Although the T and T2 genes map physically close to one another and produce very similar phenotypes, they are unrelated in sequence, which explains why T2 has escaped detection until now. In both cases the embryos die with disorganization of the posterior axis but T2 homozygotes are less affected in all measurable ways. However, T2 does not complement T, tct or the unlinked tail interaction factor (t int). Thus, we believe there must be a minimum of three genes interacting in the T pathway of axial development. The functional analysis of T2 may help clarify some of the molecular causes of spina bifida.
The quaking I-5 protein (QKI-5) has a novel nuclear localization signal and shuttles between the nucleus and the cytoplasm.
Wu, J., Zhou L., Tonissen K, Tee R., and K. Artzt.
The Journal of Biological Chemistry 274: (1999) 29202-29210.
Genomic organization and expression analysis of the mouse qKI encoding a KH domain RNA binding protein involved in myelination in CNS.
Kondo, T., T. Furuta, K. Mitsunaga, T. A. Ebersole, M. Shichiri, J. Wu, K. Artzt, K. Yamamura and K. Abe.
Mammalian Genome 10: (1999) 662-669.
The star protein QUAKING-6, is a translational repressor.
Saccomanno, L., Loushin, C, Jan, E., Punkay, E., Artzt, K. and E.B. Goodwin.
Proceedings of the National Academy Sciences USA 96: (1999) 12605-12610.
T-Star/Etoile a novel relative of SAM68 that interacts with an RNA-biding protein unique to spermatogenesis.
Venables, J. P., C. Vernet, S. L. Chew, R. B. Cowmeado, J. Wu, H. J. Cooke, K. Artzt and I. C. Eperon.
Human Molecular Genetics 8: (1999) 959-969.
Mouse Brachyury the second (T2) is a gene next to classical T and a candidate gene for tct.
Rennebeck, G., E. Lader, A. Fujimoto, E. P. Lei, and K. Artzt.
Genetics 150 (1998): 1125-1131.
STAR, a gene family involved in signal transduction and activation of RNA.
Vernet, C. and K. Artzt.
Trends in Genetics. 13 (1997): 479-484.
Neural cell type-specific expression of QKI proteins is altered in quaking viable mutant mice.
Hardy, R. J., C. L. Loushin, V. L. Friedrich, Q. Chen, T. A. Ebersole, R. A. Lazzarini, and K. Artzt.
The Journal of Neuroscience. 16 (1996): 7941-7949.
The quaking gene product necessary in embryogenesis and myelination combines features of RNA binding and signal transduction proteins.
Ebersole, T., Q. Chen, M. J. Justice, and K. Artzt.
Nature Genetics 12 (1996): 260-265
Is there a Brachyury The Second? Analysis of a transgenic mutation involved in notochord maintenance in mice.
Rennebeck, G. M., E. Lader, Q. Chen, R. A. Bohm, Z. S. Cai, C. Faust, T. Magnuson, L. R. Pease, and K. Artzt.
Developmental Biology 170 (1995): 206-217.
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