GENETIC BASIS OF SPERMATOGONIAL STEM CELL RENEWAL

Baylor College Of Medicine, Houston TX

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Abstract

PROJECT #2: The phenotype observed in developing jsd/jsd testes is one of a single postnatal wave of spermatogenesis, followed by a spermatogenic failure leading sterile males with small testis, good numbers of Sertoli cells, and a few type A spermatogonia. This defect is generally believed to be the result of failure of A-aligned (Aal) spermatogonia to differentiate into A1 spermatogonia. We have recently shown that the genetic basis for this phenotype is a small jsd specific rearrangement in the Utp14b retrogene located within the first intron of Acsl3 (Long-chain-fatty-acid CoA Ligase 3) on MMU1. Utp14b represents a retroposed copy of the X-linked Utp14a gene that itself is the mouse homolog of the yeast UTP14 gene. Whereas Utp14a is ubiquitously expressed, the retrogene Utp14b has acquired a testis specific expression pattern being expressed in germ cells from zygotene to round spermatids. UTP14 protein is an essential component of a recently discovered new cellular entity termed the small subunit (SSU)processome. This large ribonucleoprotein is bound to the U3 snoRNA and plays a key role in pre-rRNA processing and the biogenesis of ribosomes. We suggest that Utp14b having retroposed and acquired a germ cell specific expression pattern, may have provided a mechanism for increasing the efficiency and/or numbers of germ cells produced, by meeting the need for more 18s rRNA and protein during the early stages of spermatogenesis. Such a mechanism would be of obvious reproductive advantage and would be strongly selected for in evolution. Consistent with this hypothesis is the finding of a similar X-autosome retroposition of UTP14 in human, termed hUTP14c, which appears to have arisen independently of that in rodents. We have recently shown that mutations in this retrogene are associated with infertility in Man indicating that, as in mouse, human hUTP14c is crucial for normal spermatogenesis to occur: To further study the role of the UTP14 genes in mammalian spermatogenesis, the following four specific aims are proposed: (1)To address the hypothesis that Utp14b is involved in 18S rRNA production and is necessary for normal Al to A1 spermatogonial differentiation to occur;(2) To address the hypothesis that the mUtp14b retrogene may have sufficiently evolved from the original X-linked mUtp14a that it has acquired a specific function in spermatogenesis;(3) To address the hypothesis that androgen levels re-initiate spermatogenesis in jsd/jsd mice by changing the expression pattern of mUtp14 genes in the germ line;(4)To address the hypothesis that testis specific retrogenes, having been evolutionary selected for from thousands of non-functional retroposon events, will play a vital role in human spermatogenesis.