Science for Health
In 1976 a study of men with partially deleted Y chromosomes provided evidence that the human Y chromosome carries genetic information essential for male fertility; we published comparable evidence for the mouse Y in 1986. The main focus of our group is in understanding the genetic basis for this essential role, using the mouse as a model. Currently, our work is focused in three main areas:
Firstly, we are using transgenic approaches to ascribe spermatogenic functions to genes mapping to specific deletion intervals of the mouse Y chromosome that we have previously shown impact on spermatogenesis. Our first success was in 2002 when we showed that Eif2s3y is necessary for normal spermatogonial proliferation. Eif2s3y encodes a subunit of the translation initiation factor Eif2, but all other proliferating cells manage with an X-encoded copy. Recently we have identified the multi-copy Y long arm gene Sly as an important post meiotic regulator of sex chromosome gene expression, which is essential for the production of functional sperm.
Secondly, we are seeking to understand the underlying genetic causes of the sterility of males with variant Y chromosome constitutions such as XYY. We have established that an additional Y chromosome can interfere with the meiotic silencing of the Y chromosome that is a normal feature of male meiosis, and this is associated with pachytene spermatocyte death. Spermatocytes with both Y chromosomes silenced survive this stage, but the majority are then eliminated at the first meiotic metaphase – a presumed consequence of a spindle checkpoint response to univalent sex chromosomes.
Thirdly, our findings regarding the underlying causes of the sterility of sex chromosomally variant males have led us to investigate the underlying genetic basis for XY female infertility; we have implicated meiotic silencing of the single X, and inappropriate Y gene expression as causal factors.
a. Testis section from an XO mouse that is male because it carries the testis determinant Sry as a transgene. There is an early failure of spermatogenesis during spermatogonial stages. b. Addition of an Eif2s3y transgene overcomes the early spermatogonial arrest.
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