Conclusions from hESC differentiation

hESC differentiation is a promising approach to dissect genetics of human germ cell specification and differentiation. We showed that undifferentiated hESCs expressed STELLAR and DAZL but not later germ cell markers such as VASA. Given this expression pattern and the observation that in diverse organisms including flies, worms, frogs, fish, mice and humans, DAZL expression is restricted to germ cells (Xu et al., 2001). Along with additional data on embryonic expression of DAZL and STELLAR, we propose that DAZL is the earliest known marker of human germ cells. Construction of a DAZL promoter reporter system confirms expression from this promoter in hESCs and mESCs, as well as germ cells (Fig. 12.14). We expect that expression from the DAZL promoter will be maintained only in germ cells and not somatic cells upon differentiation.

Further consideration of the time course of expression of the genes OCT4, NANOG, NANOS1, STELLAR and DAZL in hESCs leads to two suggestions, also outlined in our model (Fig. 12.14): First, growth and propagation of a self-renewing population from ICM cells to form ES cells may lead to the spontaneous differentiation of all or a portion of cells to the germ cell lineage. Second, putative DAZL-and STELLAR-positive germ cells may differentiate to form both germ cells and somatic cells. These conclusions are supported by observations that the germ cell lineage is one of the first lineages to form in many organisms and does not require an intermediate embryonic precursor of ectoderm, endoderm or mesoderm lineages

Removal of positive and/or negative signal(s)

ES cells

OCT4 STELLAR NANOS

DAZL

Germ cells

VASA SCP3

Germ cell and somatic cell differentiation

Germ cell differentiation exclusively

Figure 12.14 Model of the formation and differentiation of mammalian germ cells. We hypothesize that hESCs and early germ cells are equivalent cell types, as shown, that are distinct from cells of the ICM. Cells that are positive for expression of OCT4, STELLAR, NANOS and DAZL may contribute to both germ cell and somatic cell lineages. We hypothesize that with expression of later genes such as VASA or SCP3 cells are committed to the germ cell lineage. Details are based on published results (Clark et al., 2004a,b)

(Tsang et al., 2001). Moreover, embryonic germ (EG) cell lines, derived from human PGCs in the gonadal ridge, share characteristics with ESC lines. Just as ESC lines, EG lines are pluripotent, able to self-renew and form EBs containing all major somatic lineages (Onyango et al., 2002; Shamblott et al., 1998,2001). These observations suggest that even when PGCs are in the gonad of developing humans, their potential may not yet restricted to the germ cell lineage alone. Clearly under conditions of culture, they can form germ cells or somatic cells.

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