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1412 Tang Pm 1 Int. J. Dev. Biol. 45: 549-555 (2001) Mouse PGC allocation and differentiation 549 The allocation and differentiation of mouse primordial germ cells TANIA E. TSANG1, POH-LYNN KHOO1, ROBYN V. JAMIESON1, SHEILA X. ZHOU1, SIEW-LAN ANG2, RICHARD BEHRINGER3 AND PATRICK P.L. TAM*,1 1Embryology Unit, Children’s Medical Research Institute, University of Sydney, Westmead, Australia, 2Institute of Genetics and Molecular and Cellular Biology, Illkirch, Strasbourg, France and 3Department of Molecular Genetics, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA ABSTRACT Analysis of the lineage potency of epiblast cells of the early-streak stage mouse embryo reveals that the developmental fate of the cells is determined by their position in the germ layer. Epiblast cells that are fated to become neuroectoderm can give rise to primordial germ cells (PGCs) and other types of somatic cells when they were transplanted to the proximal region of the epiblast. On the contrary, proximal epiblast cells transplanted to the distal region of the embryo do not form PGCs. Therefore, the germ line in the mouse is unlikely to be derived from a predetermined progenitor population, but may be specified as a result of tissue interactions that take place in the proximal epiblast of the mouse gastrula. The initial phase of the establishment of the PGC population requires, in addition to BMP activity emanating from the extraembryonic ectoderm, normal Lim1 and Hnf3β activity in the germ layers. The entire PGC population is derived from a finite number of progenitor cells and there is no further cellular recruitment to the germ line after gastrulation. The XX PGCs undergo X-inactivation at the onset of migration from the gut endoderm and re-activate the silenced X-chromosome when they enter the urogenital ridge. Germ cells that are localised ectopically in extragonadal sites do not re-activate the X-chromo- some, even when nearly all germ cells in the fetal ovary have restored full activity of both X- chromosomes. XXSxr germ cells can re-activate the X-chromosome in the sex-reversed testis, suggesting that the regulation of X-chromosome activity is independent of ovarian morpho- genesis. KEY WORDS: Primordial germ cells, allocation, mutant embryo, X-chromosome activity, sex reversal. Prologue Establishment of the germ cell lineage in the mouse Those of us who have had the privilege of working with Anne Primordial germ cells (PGCs) are the precursors of the oocytes McLaren or have visited her laboratory in the MRC Mammalian and spermatozoa. In the mouse, these cells can be distinguished Development Unit at University College London could recall from other embryonic cells by their strong tissue non-specific form vividly how we were captivated by Anne’s passion for the fascinat- of alkaline phosphatase (TNAP) activity on the cell membrane and ing biology of germ cell differentiation, regulation of X-chromo- peri-nuclear cytoplasmic inclusion (Ordzenski, 1967; Ginsburg et some activity and sex determination. After graduating from Anne’s al., 1990; Lawson and Hage, 1994). Cells displaying this unique laboratory, PPLT thought that he would move on to tackle other pattern of TNAP activity are first detected in the posterior region of questions on the developmental biology of the mouse, but soon the primitive streak (PS) and at the base of the allantoic bud of the found that he had to re-visit germ cells and gonad development late-streak stage embryo (Ordzenski, 1967; Ginsburg et al., 1990). many times since as a result of either an interesting discovery or mere serendipity. Our work presented in this review is the out- Abbreviations used in this paper: BMP, bone morphogenetic protein; ES, come of the active pursuit of a number of issues relating to the embryonic stem cells; ex-ect, extraembryonic ectoderm; PGC, primordial biology of the primordial germ cells at the Children’s Medical germ cell; PS, primitive streak; TNAP, tissue non-specific form of alkaline Research Institute. phosphatase. *Address correspondence to: Patrick P.L. Tam. Embryology Unit. Children’s Medical Research Institute, Locked Bag 23, Wentworthville, NSW 2145, Australia. FAX: +61-2-9681-2120. e-mail: [email protected] 0214-6282/2001/$25.00 © UBC Press Printed in Spain www.ijdb.ehu.es 550 T.E. Tsang et al. were found to be able to differentiate into cells that show the typical PGC pattern of TNAP activity. In the reciprocal transplan- tation, proximal epiblast, which presum- ably contains cells that can generate PGCs, colonized the host neural tissue but did not form PGC-like cells after they were grafted to the distal epiblast (Tam and Zhou, 1996; Table 1). These results provide compelling evidence that cells in the distal and the proximal epiblast are equally competent to form PGCs provided that they are placed in an environment that is conducive to germ cell formation. This raises the intriguing possibility that PGC formation is subject to local environ- mental influence/s that is/are unique to Fig. 1. (A,B) Localization of alkaline phosphatase the proximal epiblast. This mode of germ positive primordial germ cells (PGCs, white ar- line specification is consistent with the rowheads) in the hindgut endoderm and base of conjecture that germ cells are formed by the allantois of (A) ARC/s and (B) Lim1+/+ em- the interaction of pluripotent epiblast cells bryos. (C) Lim1+/- embryo showing PGCs in the with other non-germ line (i.e. somatic) hindgut (white arrowhead) and scattered in the cells in the early embryo (McLaren, 1981a). yolk sac (black arrowheads). (D) Lim1-/- embryo The existence of a functionally distinctive containing no PGCs in the hindgut or base of the population of germ-line cells throughout allantois (arrows). (E) Lim1-/- embryo with only a development has been postulated based few PGCs (arrowheads) and a poorly developed on the presence of cytoplasmic inclusions allantois (*). Scale bar, 50 µm. such as the nuage material, the Balbiani Clonal analysis of the lineage potency of epiblast cells has body and other similar sub-cellular structures in fertilized oocytes, revealed that some cells in the proximal epiblast of the pre- to early- blastomeres and germ cells of several mammalian embryos (de streak stage embryo can give rise to TNAP-expressing cells that Smedt et al, 2000). However, the ability to induce germ cell colonize the allantoic mesoderm and the hindgut endoderm. How- formation in epiblast cells of diverse prospective fates does not ever, descendants of these proximal epiblast cells do not contrib- support the concept of a pre-determined germ line in the mouse ute only to the presumptive PGCs but also to other somatic tissues embryo. such as the extraembryonic mesoderm. Furthermore, cells that Experimental analysis of the differentiation of germ cells in early may contribute descendants to the PGC population are not region- postimplantation mouse embryos is hampered by the paucity of alized to any area in the proximal epiblast. The localization of the reliable lineage markers for PGCs and/or their precursors. At- precursors of PGCs in the proximal epiblast suggests that only epiblast cells in this region of the early gastrula may possess the TABLE 1 germ-line potency. During development of the germ line, a POU domain gene, Oct4, has been shown to be specifically expressed THE COLONIZATION OF EXTRAEMBRYONIC AND EMBRYONIC in the PGCs and their descendants in the gonad (Scholer et al, TISSUES BY THE EPIBLAST AND EXTRAEMBRYONIC ECTODERM 1990; Pesce et al, 1998). The Oct4 gene is expressed widely in the AFTER TRANSPLANTATION TO THE EPIBLAST OF THE PRE- TO epiblast of the early gastrula and apparently shows no regionalization EARLY-STREAK STAGE MOUSE EMBRYO to the proximal epiblast. The activity of Oct4 gene, however, is Graft-derived cells Fraction of total graft-derived cells in differentially regulated by enhancer elements for general expres- Mean/embryo Total Extraembryonic Hindgut Ectodermb Posterior PGCsc sion in the epiblast and specific expression in the PGCs (Palmieri tissuesa mesoderm et al., 1994; Yeom et al, 1996). The lack of restriction of both the Proximal epiblast to proximal site (30 embryos) d PGC potency and the Oct4 expression pattern strongly suggests 77.2±10.3 2316 93.8% 0.9% 0.7% 0.5% 4.0% that in the mouse, there may not be a pre-determined germ line and Distal epiblast to proximal site (63 embryos) d the epiblast cells either acquire or retain the potency to differentiate 75.2±10.1 5329 90.6% 2.2% 0.9% 2.6% 3.7% into germ cells. Extraembryonic ectoderm to proximal site (27 embryos) The lack of a pre-determined population of PGC progenitors 85.2±12.0 2300 84.6% 4.0% 6.1% 4.7% 0.6% Distal epiblast to distal site (12 embryos) d implies that germ-cell formation is unlikely to be restricted to 70.5±17.0 846 0% 0% 96.7% 3.5% 0% subsets of epiblast cells. This idea has been verified by testing the Proximal epiblast to distal site (19 embryos) d ability of epiblast cells that are localized outside the proximal 57.2±14.6 1086 2.5% 0% 95.6% 1.4% 0.5% epiblast to form PGCs. Distal epiblast cells that normally display a aExtraembryonic mesoderm of the yolk sac, allantoic, chorion and amnion, and ectoderm of the neuroectodermal fate (Quinlan et al., 1995) were transplanted by amnion. bNeural ectoderm and surface ectoderm. clacZ-expressing cells that display the PGC- specific pattern of alkaline phosphatase activity (Ginsburg,et al., 1990; Lawson and Hage, 1994). d micro-manipulation to the proximal region of the epiblast. They Data from Tam and Zhou (1996). Mouse PGC allocation and differentiation 551 AB Fig. 2. Reduced population of primordial germ cells in (A) Lim1 and (B) Hnf3β mu- tant mouse embryos at different somite- stages.
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