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Invertebrates

Vertebrates

Primates

Primates

Germplasm Migration

Mitosis Meiosis

Figure 12.2 (A) BOL genes are conserved in all metazoans and gave rise to a gene family that contains DAZL and DAZ. Invertebrates such as flies and worms contain a single member of the DAZ/BOL gene family, non-primate vertebrates contain two members, and primates alone have DAZ genes themselves on the Y chromosome. (B) Expression and functional analyses suggest that BOL functions in meiosis, whereas DAZ and DAZL genes are required for novel vertebrate functions beginning in the earliest germ cells predicted to bind RNA; thus, these proteins may function together to regulate translation. Second, four are homologs of proteins required for germ cell development in model organisms (Chubb, 1992; Eberhart et al., 1996; Forbes and Lehmann, 1998; Ruggiu et al., 1997). Third, five proteins demonstrated biochemical interaction, passing stringent tests of interaction.

Surprisingly, in sorting through potential interacting proteins a new member of the human DAZ gene family was identified (Fig. 12.2). However, the protein encoded by this gene was more similar to Drosophila Boule, the proposed fly ortholog of DAZ, than to human DAZ or DAZL (Eberhart et al., 1996; Xu et al., 2001). We called this newly identified gene, human BOULE (BOL). The extensive similarity shared by the RNA-binding domains of fly Boule, human BOL, DAZ and DAZL distinguished these proteins as a unique germ cell protein family (Xu et al., 2001). We further characterized human BOL as reported. Notably, comparison of the expression of human and mouse BOL indicates that they share features with DAZ/DAZL but are divergent. For example, expression of all of these proteins is restricted to germ cells, with no expression in somatic cells (Cooke et al., 1996; Dorfman et al., 1999; Houston et al., 1998; Maiwald et al., 1996; Menke et al., 1997; Mita and Yamashita, 2000; Reijo et al.,

Figure 12.3 A human BOL transgene can rescue the meiotic arrest of infertile flies with a fly boule mutation. Shown is the testes of a (A) wildtype, (B) boule mutant, (C) boule mutant with a human transgene (tg) and (D) boule mutant with a fly tg. The lower panels are a higher magnification of the upper panels. Note the presence of long, filamentous sperm tails in all flies except the boule mutant with no transgene

Figure 12.3 A human BOL transgene can rescue the meiotic arrest of infertile flies with a fly boule mutation. Shown is the testes of a (A) wildtype, (B) boule mutant, (C) boule mutant with a human transgene (tg) and (D) boule mutant with a fly tg. The lower panels are a higher magnification of the upper panels. Note the presence of long, filamentous sperm tails in all flies except the boule mutant with no transgene

1996b, 2000; Ruggiu et al., 1997; Shan et al., 1996; Yen et al., 1996). Yet, DAZ and DAZL are expressed early in germ cell development and throughout development of adult germ cells (Dorfman et al., 1999; Reijo et al., 2000). In contrast, expression of BOL is restricted to meiotic cells in a pattern identical to fly boule (Cheng et al., 1998; Maines and Wasserman, 1999; Xu et al., 2001). Thus, given the similarity in expression of the human and fly genes, we tested whether human BOL could complement a fly boule mutation (Xu et al., 2003). Remarkably, we found that progression of meiosis in mutant flies carrying a human BOL transgene was indistinguishable from that observed with the fly transgene (Fig. 12.3) (Xu et al., 2003).

Results from studies briefly described above, along with previous studies on DAZL homologs in frogs and mice, suggested a resolution to the divergent functions of DAZ homologs. Essentially, BOL genes are found in all animals where, to date, they are known to function in meiosis; in contrast, DAZL genes only occur in vertebrates where they function in early germ cell development (Eberhart et al., 1996; Houston and King, 2000a; Houston et al., 1998; Karashima et al., 2000; Ruggiu et al., 1997). Finally, Y chromosome DAZ genes only occur in primates where expression and genetic data suggest they also function in early germ cell development (Reijo et al., 1995,1996a; Simoni et al., 1997).

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