Human BOULE gene rescues meiotic defects in infertile flies

Abstract

Defects in human germ cell development are common and yet little is known of genes required for germ cell development in men and women. The pathways that develop germ cells appear to be conserved broadly, at least in outline, in organisms as diverse as flies and humans beginning with allocation of cells to the germ cell lineage, migration of these cells to the fetal gonad, mitotic proliferation and meiosis of the germ cells, and maturation into sperm and eggs. In model organisms, a few thousand genes may be required for germ cell development including meiosis. To date, however, no genes that regulate critical steps of reproduction have been shown to be functionally conserved from flies to humans. This may be due in part to strong selective pressures that are thought to drive reproductive genes to high degrees of divergence. Here, we investigated the micro- and macro-evolution of the BOULE gene, a member of the human DAZ (deleted in azoospermia) gene family, within primates, within mammals and within metazoans. We report that sequence divergence of BOULE is unexpectedly low and that rapid evolution is not detectable. We extend the evolutionary analysis of BOULE to the level of phyla and show that a human BOULE transgene can advance meiosis in infertile boule mutant flies. This is the first demonstration that a human reproductive gene can rescue reproductive defects in a fly. These studies lend strong support to the idea that BOULE may encode a key conserved switch that regulates progression of germ cells through meiosis in men.

Absence of mDazl produces a final block on germ cell development at meiosis

“…For example, insertion of human DAZ or DAZL transgenes into DazlKO mice can increase the numbers of germ cells (Slee et al, 1999;Vogel et al, 2002) but is not able to restore fertility. Meiotic defects in Boule mutant Drosophila can be rescued by the Xdazl gene from frogs (Houston et al, 1998) and by a human BOULE transgene (Xu et al, 2003).…”

“…The DAZL/DAZ genes evolved after a series of gene duplications from Email: p.saunders@ed.ac.uk the ancestral Boule gene first identified in the fly (Xu et al, 2001). Although sequence divergence between Boule genes in flies and humans is low (Xu et al, 2003), DAZ and DAZL homologues have diverged rapidly in primates (Bielawski and Yang, 2001). Immunoexpression studies on sections from rodent and human testes using antibodies specific for DAZ, DAZL or BOULE have shown that all are expressed exclusively in the germline lineage although their patterns of expression are distinct (Xu et al, 2001).…”

Differential expression of fertility genes boule and dazl in Chinese sturgeon (Acipenser sinensis), a basal fish

“…Human BOULE can rescue partial testicular defects of fruit flies with boule mutant (Xu et al 2003). Furthermore, frog dazl can restore fly boule mutant to some extent, though frog dazl show a germline function different from fly boule (Houston et al 1998;Houston and King 2000).…”

Deleted in Azoospermia-Like Enhances In Vitro Derived Porcine Germ Cell Formation and Meiosis

“…The expression of DAZ family genes is specific to germ cells [12]. In addition, the role of the DAZ family on germline development appears to be conserved across species from invertebrates to mammals, which is evident by the finding that human Dazl can partially rescue the Drosophila boule mutant [13]. Disruption of the Dazl gene in mice results in a loss of germ cells and complete absence of gametes in the female, and a failure to differentiate past meiotic prophase I during spermatogenesis [8,14].…”