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Project M

Project M

 

 

Name:

Dr. Stephanie Schubert

 

Institution:

Institute of Human Genetics

 

Telephone:

0049-511-532-3874

 

Email:

schubert.steffimh-hannover.de

 

Research focus and projects:

Human TSPY, encoding the "testis-specific protein, Y-encoded" was the first gene with strictly testis-specific expression to be isolated from a mammalian Y-chromosome [1]. Human TSPY is organized as a repetitive gene family of some 30-60 members which occupy at least five distinct clusters on the long and short arm of the Y chromosome [2]. TSPY belongs to the "TTSN" superfamily, which includes SET, NAP1, CDA1, and DENTT, autosomal genes involved in cellular growth control and tumorigenesis, as well as TSPYL1 and TSPYL2, autosomal genes of hitherto unknown function [3-5]. Within the human testis, TSPY is expressed mainly in spermatogonia and there is circumstantial evidence that TSPY is involved in spermatogonial proliferation and/or differentiation [6]. It is assumed that TSPY plays a role in tumours with germ cell origins. TSPY is strongly expressed in seminoma [7] and gonadoblastoma [8], and is regarded as a candidate gene for the GBY locus, that predisposes dysgenetic gonads of 46,XY sex-reversed females to develop malignancy [9]. TSPY is repetitive in most mammalian species investigated so far, including man and other primates, bovine species, and the horse [10]. The situation in murine species is peculiar: While tspy is functional in the rat [11, 12], the Mus musculus derived laboratory mouse harbours a single-copy pseudogene that is unable to generate a functional transcript [13]. So far no efforts had been made towards establishing an animal model that is suitable for functional analysis of the Y chromosomal gene locus TSPY. We now propose to investigate TSPY function in a much more systematic way. Because the rat carries the tspy gene in a functional state, it represents a species in which an antisense transgenesis would be a feasible approach. We will generate a transgenic rat model whose tspy is suppressed by overexpression of the antisense rtspy transgene and elucidate the effects of reduced tspy in rat testis. That antisense transgensis has been quite sucessful in rats was recently shown by Shimokawa et al. [14].

 

Key References:

  1. ARNEMANN J, EPPLEN JT, COOKE HJ, SAUERMANN U, ENGEL W SCHMIDTKE J. A human Y-chromosomal DNA sequence expressed in testicular tissue. Nucleic Acids Research 1987; 15 (21):8713-8724.

  2. MANZ E, SCHNIEDERS F, MÜLLER BRECHLIN A, SCHMIDTKE J. TSPY-related sequences represent a microheterogenous gene family organized as constitutive elements in DYZ5 tandem repeat units on the human Y chromosome. Genomics 1993; 17:726-731.

  3. VOGEL T, DITTRICH O, MEHRAEIN Y, DECHEND F, SCHNIEDERS F, SCHMIDTKE J. Murine and human TSPYL genes: novel members of the TSPY-SET-NAP1L1 family. Cytogenet Cell Genet 1998; 81:265-270.

  4. CHAI Z, SARCEVIC B, MAWSON A, TOH BH. SET-related cell division autoantigen-1 (CDA1) arrests cell growth. J Biol Chem 2001; 276(36):33665-33674.

  5. OZBUN LL, YOU L, KIANG S, ANGDISEN J, MARTINEZ A, JAKOWLEW SB. Identification of differentially expressed nucleolar TGF-beta 1 target (DENTT) in human lung cancer cells that is a new member of the TSPY/SET/NAP-1 superfamily. Genomics 2001; 73(2):179-193.

  6. SCHNIEDERS F, DÖRK T, ARNEMANN J, VOGEL T, WERNER M, SCHIDTKE J. Testis-specific protein, Y-encoded (TSPY) expression in testicular tissues. Hum Mol Genet 1996; 5:1801-1807.

  7. LAU YF. Gonadoblastoma, testicular and prostate cancer, and the TSPY gene. Am J Hum Genet 1999; 64(4):921-927.

  8. HILDENBRAND R, SCHRODER W, BRUDE E, SCHEPLER A, KONIG R, STUTTE HJ, ARNEMANN J. Detection of TSPY protein in a unilateral microscopic gonadoblastoma of a Turner mosaic patient with a Y-derived marker chromosome. J Pathol 1999; 189(4):623-626.

  9. TSUCHIYA K, REIJO R, PAGE DC, DISTECHE CM. Gonadoblastoma: Molecular definition of the susceptibility region on the Y chromosome. Am J Hum Genet 1995; 57:1400-1407.

  10. VOGEL T, SCHMIDTKE J. Structure and function of TSPY, the Y-chromosome gene coding for the "testis-specific protein". Cytogenet Cell Genet 1998; 80:209-213.

  11. DECHEND F, SCHUBERT S, NANDA I, VOGEL T, SCHMID M, SCHMIDTKE J. Organization and expression of rat TSPY. Cytogenet Cell Genet 1998; 83 (3-4): 270-274.

  12. MAZEYRAT S, MITCHELL MJ. Rodent Y chromosome TSPY gene is functional in rat and non-functional in mouse. Hum Mol Genet 1998; 7(3):557-562.

  13. VOGEL T, BOETTGER-TONG H, NANDA I, DECHEND F, AGULNIK AI, BISHOP CE, SCHMID M, SCHMIDTKE J. A murine TSPY. Chrom Res 1998; 6:35-40.

  14. SHIMOKAWA I, HIGAMI Y, TSUCHIYA T, OTANI H, KOMATSU T, CHIBA T, YAMAZA H. Lifespan extension by reduction of the growth hormone-insulin-like groth factor-1 axis: relationto caloric restriction. FASEB J 2003;8.

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