Making Germ Cells from Human Embryonic Stem Cells - Male Germline Stem Cells Developmental and Regenerative Potential - page 58

sperm production in men (Reijo et al. 1995, 1996 ; Saxena et al. 1996, 2000 ).
Reijo et al. ( 1995 ) found that 10-15% of men with azoospermia or severe oli-
gospermia [fewer than 20 million sperm per ml of ejaculate; WHO ( 1999 )] had
specific deletions of the long arm of the Y chromosome. Specifically, these dele-
tions fell within the so-called Azoospermia Factor (AZF) region, and encompassed
the newly discovered gene, termed Deleted in AZoospermia or DAZ (Reijo et al.
1995, 1996 ; Saxena et al. 1996 ). The most common phenotype associated with
these deletions was the Sertoli Cell Only Syndrome, in which men are infertile, lack
sperm, and only Sertoli cells can be identified in testicular biopsies (Fig. 3.2A ). The
DAZ genes are expressed exclusively in testis, in gonocytes of the fetus and several
stages of developing sperm of the adult male (Reijo et al. 2000 ). As shown in
Fig. 3.2B the DAZ genes contain a series of 8-18 DAZ repeat elements, an RNA-
recognition motif, and presumably function as RNA-binding proteins in sperm. It
was subsequently discovered that only humans and our closest hominid relatives,
the great apes, including bonobos, chimpanzees, gorillas, and orangutans, as well
as the Old World monkeys including macaques, have the Y chromosomal DAZ genes
(Tung et al. 2006a ; Yen et al. 1996 ).

3.3.2 DAZ Family Genes Are Evolutionarily Conserved

and Function in Gametogenesis

Homologs of DAZ have been identified on human autosomal chromosomes, as well
as in numerous animal species. The human DAZ gene family now comprises at least
three members including: the Y chromosomal DAZ ; DAZL ( DAZ-Like ), the auto-
somal “father” of DAZ ; and the more recently discovered BOULE , the “grandfather”
or ancestral gene of DAZ (Fig. 3.2B ) (Saxena et al. 1996 ; Xu et al. 2001 ). DAZL is
95% identical to DAZ in protein sequence, and maps to chromosome 3, while the
ancestor gene, BOULE maps to chromosome 2 (Fig. 3.2B ). Interestingly, the
genomes of different animals possess different complements of DAZ family genes.
Thus, invertebrates such as flies and worms contain only a single DAZ homolog
boule , while vertebrates, other than catarrhine primates (Old World monkeys and
hominids) possess Boule and Dazl genes. As the DAZ gene cluster on the Y chro-
mosome most recently arose during primate evolution within the last 30-40 million
years, catarrhine primates are the only animals to possess BOULE , DAZL , and the
DAZ genes (Yen et al. 1996 ; Xu et al. 2001 ).
As discovered from recent studies of animal models, these closely related RNA-
binding proteins are universally expressed in the germ cell lineage and function in
female and/or male germ cell development and gametogenesis. Members of the
DAZ gene family are required for fertility in diverse organisms, but differ in null
phenotypes and expression patterns. In the fruit fly Drosophila , disruption of the
DAZ homolog, Boule , causes male meiotic arrest and halted spermatogenesis
(Eberhart et al. 1996 ). In the nematode worm Caenorhabditis elegans , disruption
of Boule causes meiotic arrest in oogenesis only (Karashima et al. 2000 ). In the frog