Generation and Characterization of a Transgenic Mouse with a Functional Human TSPY1

Schubert, Stephanie; Skawran, Britta; Dechend, Frank; Nayernia, Karim; Meinhardt, Andreas; Nanda, Indrajit; Schmid, Michael; Engel, Wolfgang; Schmidtke, Jörg

doi:10.1095/biolreprod.103.016501

Cited by 25 publications

(62 citation statements)

References 32 publications

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“…2B,C). These expression patterns are similar to that of a transgenic line harboring a human TSPY transgene on the Y chromosome of the host (Schubert et al, 2003). …”

supporting

confidence: 59%

“…This latter observation suggests that the Tspy gene might be active in the spermatids of the rodents. If the regulatory mechanism in the rat is preserved in the mouse, our results suggest that the 2.4-kb human promoter is properly regulated in the spermatids of transgenic mice.Studies on TSPY expression, initially postulated to be testis-specific, in the brain are somewhat limited, despite the fact that transcripts of the human TSPY transgene could be detected by the Northern hybridization technique (Schubert et al, 2003) and TSPY ESTs have also been reported in databases of brain cDNA libraries (GenBank access. nos.…”

mentioning

confidence: 99%

“…Currently, we are uncertain if any enhancer element for spermatogonial cells is present in the 2.4-kb TSPY promoter. Since animals from the transgenic line harboring the 8.5-kb (including a 2.9-kb promoter) TSPY transgene (Schubert et al, 2003) express their transgene in spermatogonial cells, as detected by immunostaining with a TSPY antibody generated by these investigators, one might argue that any spermatogonial enhancer elements could likely be present within the 500-nucleotide sequence between À2.9 kb to À2.4 kb of the human TSPY promoter.Alternatively, the difference in expression between the two studies could reflect the effects of meiotic sex chromosome inactivation (MSCI). During early meiotic prophase, the X and Y chromosomes are subjected to chromosome-wide silencing and for many genes it persists until the end of spermatogenesis.…”

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confidence: 99%

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The Role of the Y-Located TSPY Gene in Prostatic Oncongenesis

Lau¹

2006

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 5e. TASK NUMBER 5f. WORK UNIT NUMBER REPORT DATE 01-02-2006 REPORT TYPE PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERNorthern California Institute for Research and Education San Francisco, CA 94121 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTESOriginal contains colored plates: ALL DTIC reproductions will be in black and white. ABSTRACTThe TSPY gene is the only functional gene within the critical region harboring the gonadoblastoma locus on the Y chromosome (GBY). Expression studies demonstrated that it is aberrantly expressed in prostate cancer. This project is designed to address the role of this putative oncogene on the Y chromosome in this male-specific cancer. The objectives are: 1) to identify the oncogenic or tumor promoting domain in TSPY, and 2)to correlate TSPY over-expression with prostatic oncogenesis in transgenic mice. For the past year, we have examined the TSPY expression in additional 61 cases of prostate cancer and demonstrated that its expression is proportional to the degrees of malignancy of these clinical samples. Similar study of a tissue recombination model of prostate cancer demonstrated the same results, suggesting TSPY expression is intimately associated with prostate cancer. Significantly, studies of a line of transgenic mice harboring 50 copies of the human TSPY gene on their Y chromosome demonstrated that TSPYis expressed in hyperplasic regions of the prostates of old mice, resembling those of latent cancer in old men. These findings are significant, supporting the role of TSPY in the initiation of prostatic oncogenesis. For the next 12-month period, we plan to continue our characterization of our transgenic mice to confirm TSPY as an oncogene. SUBJECT TERMS INTRODUCTIONThe TSPY gene is a tandemly repeated gene on he short arm of the human Y chromosome. Genetic mapping and complet...

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“…2B,C). These expression patterns are similar to that of a transgenic line harboring a human TSPY transgene on the Y chromosome of the host (Schubert et al, 2003). …”

supporting

confidence: 59%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The Role of the Y-Located TSPY Gene in Prostatic Oncongenesis

Lau¹

2006

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“…Another study suggested that the SV40 large T antigen oncogene directed by a 1.3-kb human TSPY promoter was capable of inducing tumor formation in the pituitary gland of the host [49]. Other transgenic mice harboring multiple copies of a 8.2-kb human TSPY DNA showed a spermatogonia/spermatocytes specific expression of the transgene, similar to the human TSPY expression pattern [50]. Although the respective transgene expression could be influenced by the length of the promoter, integration sites and genetic background of the hosts, it is conceivable that a combination of species-specific cis and trans-elements are important for the differential expression of the endogenous hTSPY and rTspy in respective types of germ cells.…”

Section: Discussionmentioning

confidence: 94%

“…The human TSPY promoter is subjected to methylation that regulates its expression in certain cancer cells [48]. Despite such differences between the promoters of the rat Tspy and human TSPY, the exact mechanism(s) of their differential expression patterns cannot be unambiguously defined since various transgenic mouse studies showed variation of transgene expression patterns by the human TSPY promoter [18,49,50]. Transgenic mice harboring a human 2.4-kb TSPY promoter directed reporter gene showed a preferential transgene-expression in spermatids of the testis, similar to the rTspy expression pattern in the present study [18].…”

Section: Discussionmentioning

confidence: 99%

The rat Tspy is preferentially expressed in elongated spermatids and interacts with the core histones

Kido

Lau

2006

Biochemical and Biophysical Research Communications

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The testis specific protein Y encoded (TSPY) gene is a tandemly repeated gene on the mammalian Y chromosome. It encodes several slightly variant proteins that harbor a conserved domain of ~170 amino acids, termed TSPY/SET/NAP1 domain, capable of binding to cyclin B. The human TSPY is preferentially expressed in spermatogonia and to lesser extent the spermatids. Although rat harbors a single functional Tspy gene on its Y-chromosome, the human and rat genes differ in their expression patterns, suggesting that they might serve different or variant functions in the testis. Transcripts of rTspy were first detected in the testis of 28 days old rats, at which time the first wave of meiotic division was occurring. The rTspy protein was initially detected in stage-9 elongating spermatids and peaked at stage-13 spermatids in adult testis, but not in spermatogonia, unlike the expression pattern of the human TSPY gene. Using a GST pull-down assay, we demonstrated that rTspy could bind to the core histones H2A, H2B, H3 and H4. Rat Tspy co-localized with the histones in the cytoplasm of selected elongated spermatids. Our results suggest that the rTspy may play critical roles as a histone chaperone during maturation of the elongating spermatids in the rat testis.

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Recent developments in testicular germ cell tumor research

Geijn

Hersmus

Looijenga

2009

Birth Defects Research Pt C

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Testicular germ cell tumors of adolescents and adults (TGCTs; the so-called type II variant) are the most frequent malignancies found in Caucasian males between 20 and 40 years of age. The incidence has increased over the last decades. TGCTs are divided into seminomas and nonseminomas, the latter consisting of the subgroups embryonal carcinoma, yolk-sac tumor, teratoma, and choriocarcinoma. The pathogenesis starts in utero, involving primordial germ cells/gonocytes that are blocked in their differentiation, and develops via the precursor lesion carcinoma in situ toward invasiveness. TGCTs are totipotent and can be considered as stem cell tumors. The developmental capacity of their cell of origin, the primordial germ cells/gonocyte, is demonstrated by the different tumor histologies of the invasive TGCTs. Seminoma represents the germ cell lineage, and embryonal carcinoma is the undifferentiated component, being the stem cell population of the nonseminomas. Somatic differentiation is seen in the teratomas (all lineages), whereas yolk-sac tumors and choriocarcinoma represent extra-embryonal differentiation. Seminomas are highly sensitive to irradiation and (DNA damaging) chemotherapy, whereas most nonseminomatous elements are less susceptible to radiation, although still sensitive to chemotherapy, with the exception of teratoma. To allow early diagnosis and follow up, appropriate markers are mandatory to discriminate between the different subgroups. In this review, a summary will be given related to several recent developments in TGCT research, especially selected because of their putative clinical impact.

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Generation and Characterization of a Transgenic Mouse with a Functional Human TSPY1

Cited by 25 publications

References 32 publications

The Role of the Y-Located TSPY Gene in Prostatic Oncongenesis

The Role of the Y-Located TSPY Gene in Prostatic Oncongenesis

The rat Tspy is preferentially expressed in elongated spermatids and interacts with the core histones

Recent developments in testicular germ cell tumor research

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