211:
expressed in the posterior visceral endoderm of the epiblast. WNT3 signalling has been shown to be essential in order for the epiblast to acquire responsiveness to the BMP4 signal from the ExE. WNT3 mutants fail to establish a primordial germ cell population, but this can be restored with exogenous WNT activity. The WNT3/β-catenin signalling pathway is essential for the expression of the transcription factor T (Brachyury), a transcription factor that was previously characterized somatic and mesoderm specific genes. T was recently found to be both necessary and sufficient to induce the expression of the known PGC specification genes Blimp1 and Prdm14. The induction of
Transcription Factor T was seen 12 hours after BMP/WNT signaling, as opposed to the 24 to 36 hours it took for Blimp1 and Prdm14 genes to be expressed. Transcription factor T acts upstream of BLIMP1 and Prdm14 in PGC specification by binding to the genes respective enhancer elements. It is important to note that while T can activate the expression of Blimp1 and Prdm14 in the absence of both BMP4 and WNT3, pre-exposure of PGC progenitors to WNTs (without BMP4) prevents T from activating these genes. Details on how BMP4 prevents T from inducing mesodermal genes, and only activate PGC specification genes, remain unclear.
252:
The efficiency of this process was later enhanced by the addition of stem cell factor (SCF), epidermal growth factor (EGF), leukaemia inhibitory factor (LIF) and BMP8B. PGC-like cells generated using this method can be transplanted into a gonad, where the differentiate, and are able to give viable gametes and offspring in vivo. PGC-like cells can also be generated from naïve embryonic stem cells (ESCs) that are cultured for two days in the presence of FGF and
Activin-A to adopt an epiblast-like state. These cells are then cultured with BMP4, BMP8B, EGF, LIF and SCF and various cytokines for four more days. These in-vitro generated PGCs can also develop into viable gametes and offspring.
99:, nanos and germ cell-less (gcl) have important roles. Oskar is sufficient to recruit the other genes to form functional germ plasm. Nanos is required to prevent mitosis and somatic differentiation and for the pole cells to migrate to function as PGCs (see next section). Gcl is necessary (but not sufficient) for pole cell formation. In addition to these genes, Pgc polar granule component blocks phosphorylation and consequently activation of RNA polymerase II and shuts down transcription.
268:. Similar findings in other vertebrates indicate that PGCs are not yet irreversibly committed to produce gametes, and no other cell type. On arrival at the gonads, human and mouse PGCs activate widely conserved germ cell-specific factors, and subsequently down-regulate the expression of pluripotency factors. This transition results in the determination of germ cells, a form of cell commitment that is no longer reversible.
188:
E7.5 a founding population of approximately 40 PGCs are generated in this region of the epiblast in the developing mouse embryo. The epiblast, however, also give rise to somatic cell lineages that make up the embryo proper; including the endoderm, ectoderm and mesoderm. The specification of primordial germ cells in mammals is mainly attributed to the downstream functions of two signaling pathways; the
95:, Tudor, vasa, and Valois). These genes play a role in germ line development to localize nanos mRNA to the posterior and localize germ cell determinants. Drosophila progeny with mutations in these genes fail to produce pole cells and are thus sterile, giving these mutations the name 'grandchildless'. The genes
251:
With the vast knowledge about in-vivo PGC specification collected over the last few decades, several attempts to generate in-vitro PGCs from post-implantation epiblast were made. Various groups were able to successfully generate PGC-like cells, cultured in the presence of BMP4 and various cytokines.
187:
Mammalian PGCs are specified by signalling between cells (induction), rather than by the segregation of germ plasm as the embryo divides. In mice, PGCs originate from the proximal epiblast, close to the extra-embryonic ectoderm (ExE), of the post-implantation embryo as early as embryonic day 6.5. By
107:
Similar germ plasm has been identified in
Amphibians in the polar cytoplasm at the vegetal pole. This cytoplasm moves to the bottom of the blastocoel and eventually ends up as its own subset of endodermal cells. While specified to produce germ cells, the germ plasm does not irreversibly commit these
121:
The first phase of migration in
Drosophila occurs when the pole cells move passively and infold into the midgut invagination. Active migration occurs through repellents and attractants. The expression of wunen in the endoderm repels the PGCs out. The expression of columbus and hedgehog attracts the
214:
Expression of Blimp1 is the earliest known marker of PGC specification. A mutation in the Blimp1 gene results in the formation of PGC-like cells at embryonic day 8.5 that closely resemble their neighbouring somatic cells. A central role of Blimp 1 is the induction of Tcfap2c, a helix-span helix
425:
while in the embryo. All of the oogonia and many primary oocytes die before birth. After puberty in primates, small groups of oocytes and follicles prepare for ovulation by advancing to metaphase II. Only after fertilization is meiosis completed. Meiosis is asymmetric producing polar bodies and
219:
of all the necessary genes to regulate PGC specification. Mutation of Prdm14 results in the formation of PGCs that are lost by embryonic day 11.5. The loss of PGCs in the Prdm14 mutant is due to failure in global erasure of histone 3 methylation patterns. Blimp1 and Prdm14 also elicit another
210:
and Prdm14 in a dose-dependent manner. This is evident as the number of PGCs forming in the epiblast decreases in proportion to the loss of BMP4 alleles. BMP4 acts through its downstream intercellular transcription factors SMAD1 and SMAD5. During approximately the same time, WNT3 starts to be
284:
once they cease migration and undergo mitosis. The term gonocyte is generally used to describe all stages post PGC until the gonocytes differentiate into spermatogonia. Anatomically, gonocytes can be identified as large, euchromatic cells that often have two nucleoli in the nucleus.
426:
oocytes with large amounts of material for embryonic development. The mutation frequency of female mouse germ line cells, like male germ line cells, is also lower than that of somatic cells. Low germ line mutation frequency appears to be due, in part, to elevated levels of
146:
In birds, the PGCs arise from the epiblast and migrate to anteriorly of the primitive streak to the germinal crest. From there, they use blood vessels to find their way to the gonad. The CXCR4/Sdf1 system is also used, though may not be the only method necessary.
215:
transcription factor. Tcfap2c mutants exhibited an early loss of primordial germ cells. Tcfap2c is thought to repress somatic gene expression, including the mesodermal marker Hoxb1. So, Blimp1, Tcfap2c and Prdm14 together are able to activate and repress the
271:
Prior to their occupation of the genital ridge, there is no known difference between XX and XY PGCs. However, once migration is complete and germ cell determination has occurred, these germline cells begin to differentiate according to the gonadal niche.
79:
Germ plasm has been studied in detail in
Drosophila. The posterior pole of the embryo contains necessary materials for the fertility of the fly. This cytoplasm, pole plasm, contains specialized materials called polar granules and the
320:. To differentiate into spermatogonia, the gonocytes must lose their junctions to Sertoli cells and become migratory once again. They migrate to the basement membrane of the seminiferous cord and differentiate.
130:
In zebrafish, the PGCs express two CXCR4 transmembrane receptor proteins. The signaling system involving this protein and its ligand, Sdf1, is necessary and sufficient to direct PGC migration in fish.
300:
coding region can lead to female development in XY individuals. Sertoli cells also act to prevent gonocytes from differentiating prematurely. They produce the enzyme CYP26B1 to counteract surrounding
138:
In frogs, the PGCs migrate along the mesentery to the gonadal mesoderm facilitated by orientated extracellular matrix with fibronectin. There is also evidence for the CXCR4/Sdf1 system in frogs.
122:
PGCs to the mesodermal precursors of the gonad. Nanos is required during migration. Regardless of PGC injection site, PGCs are able to correctly migrate to their target sites.
179:
and β1-Integrin to guide the migration of PGCs. Around 10 days post conception; the PGCs occupy the genital ridge where they begin to lose their motility and polarized shape.
470:
Wylie CC, Holwill S, O'Driscoll M, Snape A, Heasman J (1985-01-01). "Germ plasm and germ cell determination in
Xenopus laevis as studied by cell transplantation analysis".
175:
where the somatic gonadal precursors reside. This migration requires a series of attractant and repellent cues as well as a number of adhesion molecules such as
1671:
Ohinata Y, Payer B, O'Carroll D, Ancelin K, Ono Y, Sano M, et al. (July 2005). "Blimp1 is a critical determinant of the germ cell lineage in mice".
63:
from other cells. The germ plasm effectively turns off gene expression to render the genome of the cell inert. Cells expressing germ plasm become
1055:
918:
2853:
1536:
Herrmann BG, Labeit S, Poustka A, King TR, Lehrach H (February 1990). "Cloning of the T gene required in mesoderm formation in the mouse".
328:
In the gonads, the germ cells undergo either spermatogenesis or oogenesis depending on whether the sex is male or female respectively.
417:
committed to meiosis. Unlike sperm production, oocyte production is not continuous. These primary oocytes begin meiosis but pause in
2458:
1345:
Liu P, Wakamiya M, Shea MJ, Albrecht U, Behringer RR, Bradley A (August 1999). "Requirement for Wnt3 in vertebrate axis formation".
260:
Prior to their arrival at the gonads, PGCs express pluripotency factors, generate pluripotent cell lines in cell culture (known as
431:
2133:
Resnick JL, Bixler LS, Cheng L, Donovan PJ (October 1992). "Long-term proliferation of mouse primordial germ cells in culture".
1257:"Cooperation of endoderm-derived BMP2 and extraembryonic ectoderm-derived BMP4 in primordial germ cell generation in the mouse"
3170:
819:
Chiquoine AD (February 1954). "The identification, origin, and migration of the primordial germ cells in the mouse embryo".
2440:
231:, Stella and Fragilis. At the same time, Blimp1 and Prdm14 also repress the transcription of programs that drive somatic
296:
which then act as the organizing center for testis differentiation. Point mutations or deletions in the human or mouse
3138:
3083:
2862:
71:. The germ line development in mammals, on the other hand, occurs by induction and not by an endogenous germ plasm.
189:
1431:"Dullard/Ctdnep1 modulates WNT signalling activity for the formation of primordial germ cells in the mouse embryo"
297:
289:
3175:
3143:
3055:
2940:
2846:
232:
216:
36:
999:"Anatomy of a blastocyst: cell behaviors driving cell fate choice and morphogenesis in the early mouse embryo"
163:
of the embryo and start to migrate around 6.25 days after conception. PGCs start to migrate to the embryonic
2907:
2290:
Gross-Thebing T, Yigit S, Pfeiffer J, Reichman-Fried M, Bandemer J, Ruckert C, et al. (December 2017).
379:
2292:"The Vertebrate Protein Dead End Maintains Primordial Germ Cell Fate by Inhibiting Somatic Differentiation"
3128:
3027:
239:. In this way, Blimp1 and Prdm14 drive PGC specification by promoting germ line development and potential
228:
668:"Building the mammalian testis: origins, differentiation, and assembly of the component cell populations"
3133:
3123:
2967:
202:
is released by the extra-embryonic ectoderm (ExE) at embryonic day 5.5 to 5.75 directly adjacent to the
193:
64:
40:
20:
2831:
2331:
Chatfield J, O'Reilly MA, Bachvarova RF, Ferjentsik Z, Redwood C, Walmsley M, et al. (June 2014).
1225:
863:
556:"C-X-C chemokine receptor type 4 (CXCR4) is a key receptor for chicken primordial germ cell migration"
2640:
2393:
2244:
2142:
2001:
1944:
1887:
1680:
1545:
1497:"A mesodermal factor, T, specifies mouse germ cell fate by directly activating germline determinants"
1442:
261:
87:
Pole plasm is organized by and contains the proteins and mRNA of the posterior group genes (such as
2877:
2839:
2094:"Reconstitution of the mouse germ cell specification pathway in culture by pluripotent stem cells"
1823:
Weber S, Eckert D, Nettersheim D, Gillis AJ, Schäfer S, Kuckenberg P, et al. (January 2010).
1587:
Naiche LA, Harrelson Z, Kelly RG, Papaioannou VE (2005). "T-box genes in vertebrate development".
1226:"Proliferation and migration of primordial germ cells during compensatory growth in mouse embryos"
901:
Lawson KA, Hage WJ (1994). "Clonal
Analysis of the Origin of Primordial Germ Cells in the Mouse".
2213:
2166:
1704:
1612:
1569:
1370:
1327:
936:
844:
749:
2686:
Delabaere L, Ertl HA, Massey DJ, Hofley CM, Sohail F, Bienenstock EJ, et al. (April 2017).
2186:"Derivation of pluripotential embryonic stem cells from murine primordial germ cells in culture"
1773:"A tripartite transcription factor network regulates primordial germ cell specification in mice"
1771:
Magnúsdóttir E, Dietmann S, Murakami K, Günesdogan U, Tang F, Bao S, et al. (August 2013).
2688:"Aging impairs double-strand break repair by homologous recombination in Drosophila germ cells"
2333:"Stochastic specification of primordial germ cells from mesoderm precursors in axolotl embryos"
3106:
2892:
2882:
2818:
2766:
2717:
2668:
2609:
2555:
2514:
2454:
2421:
2362:
2313:
2272:
2205:
2158:
2115:
2071:
2027:
1970:
1913:
1856:
1802:
1753:
1696:
1653:
1604:
1561:
1518:
1470:
1411:
1390:"Primitive streak formation in mice is preceded by localized activation of Brachyury and Wnt3"
1362:
1319:
1278:
1237:
1206:
1165:
1134:
Lawson KA, Dunn NR, Roelen BA, Zeinstra LM, Davis AM, Wright CV, et al. (February 1999).
1111:
1051:
1028:
979:
924:
914:
883:
836:
801:
741:
697:
645:
587:
536:
487:
32:
1185:"SMAD1 signaling is critical for initial commitment of germ cell lineage from mouse epiblast"
3045:
3008:
2989:
2808:
2800:
2756:
2748:
2707:
2699:
2658:
2648:
2629:"Mutation frequency declines during spermatogenesis in young mice but increases in old mice"
2599:
2589:
2545:
2504:
2446:
2411:
2401:
2352:
2344:
2303:
2262:
2252:
2197:
2150:
2105:
2061:
2017:
2009:
1960:
1952:
1903:
1895:
1846:
1836:
1792:
1784:
1743:
1735:
1688:
1643:
1596:
1553:
1508:
1495:
Aramaki S, Hayashi K, Kurimoto K, Ohta H, Yabuta Y, Iwanari H, et al. (December 2013).
1460:
1450:
1401:
1354:
1309:
1268:
1196:
1155:
1147:
1101:
1093:
1018:
1010:
997:
Schrode N, Xenopoulos P, Piliszek A, Frankenberg S, Plusa B, Hadjantonakis AK (April 2013).
971:
906:
875:
828:
791:
783:
731:
687:
679:
635:
627:
577:
567:
526:
518:
479:
434:. Enhanced genetic integrity may be a fundamental characteristic of germ line development.
160:
2737:"Evidence for paternal age-related alterations in meiotic chromosome dynamics in the mouse"
2578:"Paracrine mechanisms involved in the control of early stages of Mammalian spermatogenesis"
1933:"Genome-wide reprogramming in the mouse germ line entails the base excision repair pathway"
1874:
Hajkova P, Ancelin K, Waldmann T, Lacoste N, Lange UC, Cesari F, et al. (April 2008).
1600:
2922:
2185:
948:
448:
388:
363:
337:
1990:"Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine"
1988:
Hackett JA, Sengupta R, Zylicz JJ, Murakami K, Lee C, Down TA, Surani MA (January 2013).
2644:
2397:
2380:
Nicholls PK, Schorle H, Naqvi S, Hu YC, Fan Y, Carmell MA, et al. (November 2019).
2248:
2146:
2005:
1948:
1891:
1684:
1549:
1446:
616:"Mechanisms guiding primordial germ cell migration: strategies from different organisms"
3101:
2999:
2813:
2788:
2761:
2736:
2712:
2687:
2604:
2577:
2416:
2381:
2357:
2332:
2267:
2232:
2022:
1989:
1965:
1932:
1908:
1875:
1797:
1772:
1465:
1430:
1106:
1081:
1023:
998:
796:
771:
692:
667:
640:
615:
582:
555:
531:
506:
355:
24:
1748:
1723:
1429:
Tanaka SS, Nakane A, Yamaguchi YL, Terabayashi T, Abe T, Nakao K, et al. (2013).
1201:
1184:
1160:
1135:
3164:
3050:
2994:
2663:
2628:
2201:
787:
347:
343:
309:
301:
293:
243:
transcriptional programs while also keeping the cells from taking on a somatic fate.
172:
2217:
1739:
1374:
1331:
848:
753:
3065:
3020:
3015:
2493:"Gonocytes, from the fifties to the present: is there a reason to change the name?"
2170:
1708:
1616:
1573:
371:
240:
96:
88:
2804:
2509:
2492:
1841:
1825:"Critical function of AP-2 gamma/TCFAP2C in mouse embryonic germ cell maintenance"
1824:
1183:
Hayashi K, Kobayashi T, Umino T, Goitsuka R, Matsui Y, Kitamura D (October 2002).
1136:"Bmp4 is required for the generation of primordial germ cells in the mouse embryo"
2382:"Mammalian germ cells are determined after PGC colonization of the nascent gonad"
2308:
2291:
1513:
1496:
1455:
905:. Novartis Foundation Symposia. Vol. 182. pp. 68–84, discussion 84–91.
3060:
2985:
2927:
2752:
1406:
1389:
1097:
975:
483:
359:
176:
2633:
Proceedings of the
National Academy of Sciences of the United States of America
2386:
Proceedings of the
National Academy of Sciences of the United States of America
2237:
Proceedings of the
National Academy of Sciences of the United States of America
2110:
2093:
2066:
2049:
1648:
1631:
1298:"Requirement of Bmp8b for the generation of primordial germ cells in the mouse"
3116:
3003:
2977:
2917:
2912:
2897:
2050:"A signaling principle for the specification of the germ cell lineage in mice"
910:
427:
384:
351:
92:
60:
2653:
2594:
2450:
1724:"Transcription factor gene AP-2 gamma essential for early murine development"
962:
Lanner F (February 2014). "Lineage specification in the early mouse embryo".
391:
declines with advancing paternal age likely due to an increased frequency of
2949:
2406:
2257:
2013:
1956:
1931:
Hajkova P, Jeffries SJ, Lee C, Miller N, Jackson SP, Surani MA (July 2010).
443:
422:
418:
404:
281:
236:
156:
81:
2822:
2770:
2721:
2613:
2559:
2518:
2425:
2366:
2317:
2276:
2119:
2075:
2048:
Ohinata Y, Ohta H, Shigeta M, Yamanaka K, Wakayama T, Saitou M (May 2009).
2031:
1974:
1917:
1876:"Chromatin dynamics during epigenetic reprogramming in the mouse germ line"
1860:
1806:
1757:
1700:
1657:
1608:
1522:
1474:
1415:
1366:
1323:
1314:
1297:
1282:
1273:
1256:
1210:
1169:
1115:
1032:
983:
840:
745:
701:
683:
649:
591:
540:
2672:
2209:
2162:
1565:
1241:
928:
887:
879:
832:
805:
491:
3093:
3075:
3037:
2954:
2787:
Murphey P, McLean DJ, McMahan CA, Walter CA, McCarrey JR (January 2013).
1151:
572:
367:
317:
313:
265:
203:
164:
48:
2627:
Walter CA, Intano GW, McCarrey JR, McMahan CA, Walter RB (August 1998).
1899:
1692:
2703:
2348:
414:
410:
392:
305:
168:
68:
28:
2550:
2533:
1851:
1014:
736:
719:
3111:
2902:
2887:
2154:
1557:
465:
463:
1788:
631:
522:
366:
at different stages of development in the mouse have a frequency of
206:
and causes the region of the epiblast nearest to the ExE to express
223:
Other notable genes positively regulated by Blimp1 and Prdm14 are:
2092:
Hayashi K, Ohta H, Kurimoto K, Aramaki S, Saitou M (August 2011).
1358:
554:
Lee, JH; Park, JW; Kim, SW; Park, J; Park, TS (15 December 2017).
350:
committed to meiosis. The spermatocytes divide by meiosis to form
207:
44:
224:
199:
2835:
2442:
From Egg to Embryo: Regional Specification in Early Development
864:"Primordial germ cells in the mouse embryo during gastrulation"
2233:"Spontaneous Testicular Teratomas in an Inbred Strain of Mice"
2735:
Vrooman LA, Nagaoka SI, Hassold TJ, Hunt PA (February 2014).
304:. Retinoic acid acts as a signal to the gonocytes to enter
1296:
Ying Y, Liu XM, Marble A, Lawson KA, Zhao GQ (July 2000).
370:
that is 5 to 10-fold lower than the mutation frequency in
308:. The gonocyte and Sertoli cells have been shown to form
292:
expression causes supporting cells to differentiate into
718:
Ewen-Campen B, Schwager EE, Extavour CG (January 2010).
220:
epigenetic event that causes global DNA demethylation.
59:
Cleavage in most animals segregates cells containing
903:
Ciba Foundation Symposium 182 - Germline Development
720:"The molecular machinery of germ line specification"
383:, the ability of premeiotic male germ line cells to
354:. The post-meiotic spermatids differentiate through
16:
How an animal develops its sexual-reproduction cells
3092:
3074:
3036:
2976:
2963:
2936:
2870:
776:
Electroencephalography and Clinical Neurophysiology
472:
Cold Spring Harbor Symposia on Quantitative Biology
264:,) and can produce multi-lineage tumors, known as
1630:Cinalli RM, Rangan P, Lehmann R (February 2008).
1230:Journal of Embryology and Experimental Morphology
1050:(10th ed.). Sunderland: Sinauer Associates.
108:cells to produce gametes and no other cell type.
2789:"Enhanced genetic integrity in mouse germ cells"
55:Creation of germ plasm and primordial germ cells
2782:
2780:
2571:
2569:
2486:
2484:
2482:
2480:
2478:
2476:
2087:
2085:
2043:
2041:
1818:
1816:
1490:
1488:
1486:
1484:
1129:
1127:
1125:
862:Ginsburg M, Snow MH, McLaren A (October 1990).
2184:Matsui Y, Zsebo K, Hogan BL (September 1992).
661:
659:
609:
607:
605:
603:
601:
2847:
1388:Rivera-Pérez JA, Magnuson T (December 2005).
713:
711:
84:are the precursors to primordial germ cells.
8:
765:
763:
560:The Journal of Reproduction and Development
2973:
2854:
2840:
2832:
1086:Cold Spring Harbor Perspectives in Biology
770:Magnúsdóttir E, Surani MA (Jan 21, 2014).
507:"Specifying and protecting germ cell fate"
430:enzymes that remove potentially mutagenic
387:declines dramatically with age. In mouse,
312:as well as adherins junctions composed of
2812:
2760:
2711:
2662:
2652:
2603:
2593:
2549:
2508:
2415:
2405:
2356:
2307:
2266:
2256:
2109:
2065:
2021:
1964:
1907:
1850:
1840:
1796:
1747:
1647:
1512:
1464:
1454:
1405:
1313:
1272:
1200:
1159:
1105:
1075:
1073:
1071:
1069:
1067:
1022:
795:
735:
691:
639:
614:Richardson BE, Lehmann R (January 2010).
581:
571:
530:
256:Differentiation of primordial germ cells
67:(PGCs) which will then give rise to the
2534:"Genetic control of testis development"
2231:Stevens LC, Little CC (November 1954).
459:
413:, divide by mitosis to produce primary
35:. During development, these cells will
1601:10.1146/annurev.genet.39.073003.105925
944:
934:
724:Molecular Reproduction and Development
666:Svingen T, Koopman P (November 2013).
620:Nature Reviews. Molecular Cell Biology
511:Nature Reviews. Molecular Cell Biology
288:In the male genital ridge, transient
247:Generation of mammalian PGCs in vitro
7:
1080:Saitou M, Yamaji M (November 2012).
772:"How to make a primordial germ cell"
235:by inhibiting transcription of the
200:Bone morphogenetic protein 4 (BMP4)
2576:Rossi P, Dolci S (November 2013).
112:Migration of primordial germ cells
14:
2532:Sekido R, Lovell-Badge R (2013).
1722:Werling U, Schorle H (May 2002).
43:, migrate to the location of the
505:Strome S, Updike D (July 2015).
358:to become mature and functional
1740:10.1128/mcb.22.9.3149-3156.2002
1224:Tam PP, Snow MH (August 1981).
1082:"Primordial germ cells in mice"
346:, divide by mitosis to produce
310:gap and desmosomelike junctions
194:canonical WNT/β-catenin pathway
183:Germline development in mammals
171:and finally towards the future
1728:Molecular and Cellular Biology
1255:Ying Y, Zhao GQ (April 2001).
1:
2805:10.1095/biolreprod.112.103481
2510:10.1095/biolreprod.113.110544
1842:10.1095/biolreprod.109.078717
1202:10.1016/S0925-4773(02)00237-X
2439:Slack, J. M. W. (May 1991).
2309:10.1016/j.devcel.2017.11.019
2202:10.1016/0092-8674(92)90317-6
1514:10.1016/j.devcel.2013.11.001
1456:10.1371/journal.pone.0057428
788:10.1016/0013-4694(87)90100-3
157:primordial germ cells (PGCs)
3139:Splanchnopleuric mesenchyme
3084:Splanchnopleuric mesenchyme
2863:Human embryonic development
2753:10.1534/genetics.113.158782
1407:10.1016/j.ydbio.2005.09.012
1098:10.1101/cshperspect.a008375
976:10.1016/j.yexcr.2013.12.004
484:10.1101/SQB.1985.050.01.007
385:repair double-strand breaks
31:are often set aside during
3192:
2582:Frontiers in Endocrinology
2111:10.1016/j.cell.2011.06.052
2067:10.1016/j.cell.2009.03.014
1649:10.1016/j.cell.2008.02.003
1046:Gilbert, Scott F. (2013).
964:Experimental Cell Research
402:
335:
280:Male PGCs become known as
276:Early male differentiation
192:signaling pathway and the
1589:Annual Review of Genetics
1189:Mechanisms of Development
911:10.1002/9780470514573.ch5
409:Mitotic germ stem cells,
342:Mitotic germ stem cells,
3144:Somatopleuric mesenchyme
3056:Somatopleuric mesenchyme
2865:in the first three weeks
2654:10.1073/pnas.95.17.10015
2595:10.3389/fendo.2013.00181
2451:10.1017/cbo9780511525322
1632:"Germ cells are forever"
103:Germ plasm in amphibians
2793:Biology of Reproduction
2497:Biology of Reproduction
2491:Culty M (August 2013).
2407:10.1073/pnas.1910733116
2258:10.1073/pnas.40.11.1080
2014:10.1126/science.1229277
1957:10.1126/science.1187945
1829:Biology of Reproduction
1302:Molecular Endocrinology
1140:Genes & Development
672:Genes & Development
159:arise in the posterior
75:Germ plasm in fruit fly
3028:Regional specification
1315:10.1210/mend.14.7.0479
1274:10.1006/dbio.2001.0173
684:10.1101/gad.228080.113
27:that give rise to the
3171:Developmental biology
3134:Intraembryonic coelom
1394:Developmental Biology
1261:Developmental Biology
1048:Developmental biology
880:10.1242/dev.110.2.521
833:10.1002/ar.1091180202
821:The Anatomical Record
65:primordial germ cells
41:primordial germ cells
21:developmental biology
1152:10.1101/gad.13.4.424
573:10.1262/jrd.2017-067
324:Late differentiation
2645:1998PNAS...9510015W
2398:2019PNAS..11625677N
2392:(51): 25677–25687.
2249:1954PNAS...40.1080S
2147:1992Natur.359..550R
2006:2013Sci...339..448H
1949:2010Sci...329...78H
1900:10.1038/nature06714
1892:2008Natur.452..877H
1777:Nature Cell Biology
1693:10.1038/nature03813
1685:2005Natur.436..207O
1550:1990Natur.343..617H
1447:2013PLoSO...857428T
364:Spermatogenic cells
2704:10.1111/acel.12556
2538:Sexual Development
2445:. Cambridge Core.
2349:10.1242/dev.105346
2296:Developmental Cell
1501:Developmental Cell
33:embryonic cleavage
3158:
3157:
3154:
3153:
2883:Oocyte activation
2551:10.1159/000342221
2302:(6): 704–715.e5.
1057:978-1-60535-173-5
1015:10.1002/dvg.22368
920:978-0-470-51457-3
737:10.1002/mrd.21091
3183:
3046:Surface ectoderm
3009:Primitive groove
2990:Primitive streak
2974:
2856:
2849:
2842:
2833:
2827:
2826:
2816:
2784:
2775:
2774:
2764:
2732:
2726:
2725:
2715:
2683:
2677:
2676:
2666:
2656:
2624:
2618:
2617:
2607:
2597:
2573:
2564:
2563:
2553:
2529:
2523:
2522:
2512:
2488:
2471:
2470:
2468:
2467:
2436:
2430:
2429:
2419:
2409:
2377:
2371:
2370:
2360:
2328:
2322:
2321:
2311:
2287:
2281:
2280:
2270:
2260:
2228:
2222:
2221:
2181:
2175:
2174:
2155:10.1038/359550a0
2130:
2124:
2123:
2113:
2089:
2080:
2079:
2069:
2045:
2036:
2035:
2025:
2000:(6118): 448–52.
1985:
1979:
1978:
1968:
1928:
1922:
1921:
1911:
1886:(7189): 877–81.
1871:
1865:
1864:
1854:
1844:
1820:
1811:
1810:
1800:
1768:
1762:
1761:
1751:
1719:
1713:
1712:
1679:(7048): 207–13.
1668:
1662:
1661:
1651:
1627:
1621:
1620:
1584:
1578:
1577:
1558:10.1038/343617a0
1544:(6259): 617–22.
1533:
1527:
1526:
1516:
1492:
1479:
1478:
1468:
1458:
1426:
1420:
1419:
1409:
1385:
1379:
1378:
1342:
1336:
1335:
1317:
1293:
1287:
1286:
1276:
1252:
1246:
1245:
1221:
1215:
1214:
1204:
1180:
1174:
1173:
1163:
1131:
1120:
1119:
1109:
1077:
1062:
1061:
1043:
1037:
1036:
1026:
994:
988:
987:
959:
953:
952:
946:
942:
940:
932:
898:
892:
891:
859:
853:
852:
816:
810:
809:
799:
767:
758:
757:
739:
715:
706:
705:
695:
663:
654:
653:
643:
611:
596:
595:
585:
575:
551:
545:
544:
534:
502:
496:
495:
467:
237:Hox family genes
167:and then to the
161:primitive streak
3191:
3190:
3186:
3185:
3184:
3182:
3181:
3180:
3176:Germ line cells
3161:
3160:
3159:
3150:
3088:
3070:
3032:
2965:
2959:
2938:
2932:
2923:Inner cell mass
2866:
2860:
2830:
2786:
2785:
2778:
2734:
2733:
2729:
2685:
2684:
2680:
2639:(17): 10015–9.
2626:
2625:
2621:
2575:
2574:
2567:
2531:
2530:
2526:
2490:
2489:
2474:
2465:
2463:
2461:
2438:
2437:
2433:
2379:
2378:
2374:
2343:(12): 2429–40.
2330:
2329:
2325:
2289:
2288:
2284:
2230:
2229:
2225:
2183:
2182:
2178:
2141:(6395): 550–1.
2132:
2131:
2127:
2091:
2090:
2083:
2047:
2046:
2039:
1987:
1986:
1982:
1943:(5987): 78–82.
1930:
1929:
1925:
1873:
1872:
1868:
1822:
1821:
1814:
1789:10.1038/ncb2798
1770:
1769:
1765:
1721:
1720:
1716:
1670:
1669:
1665:
1629:
1628:
1624:
1586:
1585:
1581:
1535:
1534:
1530:
1494:
1493:
1482:
1428:
1427:
1423:
1387:
1386:
1382:
1347:Nature Genetics
1344:
1343:
1339:
1295:
1294:
1290:
1254:
1253:
1249:
1223:
1222:
1218:
1195:(1–2): 99–109.
1182:
1181:
1177:
1133:
1132:
1123:
1092:(11): a008375.
1079:
1078:
1065:
1058:
1045:
1044:
1040:
996:
995:
991:
961:
960:
956:
943:
933:
921:
900:
899:
895:
861:
860:
856:
818:
817:
813:
769:
768:
761:
717:
716:
709:
678:(22): 2409–26.
665:
664:
657:
632:10.1038/nrm2815
613:
612:
599:
553:
552:
548:
523:10.1038/nrm4009
504:
503:
499:
469:
468:
461:
457:
449:Germ cell tumor
440:
407:
401:
389:spermatogenesis
340:
338:Spermatogenesis
334:
332:Spermatogenesis
326:
278:
258:
249:
233:differentiation
185:
153:
144:
136:
128:
119:
114:
105:
77:
57:
51:of the animal.
47:, and form the
17:
12:
11:
5:
3189:
3187:
3179:
3178:
3173:
3163:
3162:
3156:
3155:
3152:
3151:
3149:
3148:
3147:
3146:
3141:
3136:
3126:
3121:
3120:
3119:
3114:
3104:
3102:Axial mesoderm
3098:
3096:
3090:
3089:
3087:
3086:
3080:
3078:
3072:
3071:
3069:
3068:
3063:
3058:
3053:
3048:
3042:
3040:
3034:
3033:
3031:
3030:
3025:
3024:
3023:
3013:
3012:
3011:
3006:
3000:Primitive node
2997:
2982:
2980:
2971:
2961:
2960:
2958:
2957:
2952:
2946:
2944:
2934:
2933:
2931:
2930:
2925:
2920:
2915:
2910:
2905:
2900:
2895:
2890:
2885:
2880:
2874:
2872:
2868:
2867:
2861:
2859:
2858:
2851:
2844:
2836:
2829:
2828:
2776:
2727:
2698:(2): 320–328.
2678:
2619:
2565:
2544:(1–3): 21–32.
2524:
2472:
2459:
2431:
2372:
2323:
2282:
2243:(11): 1080–7.
2223:
2176:
2125:
2081:
2037:
1980:
1923:
1866:
1812:
1763:
1734:(9): 3149–56.
1714:
1663:
1622:
1579:
1528:
1480:
1421:
1380:
1337:
1308:(7): 1053–63.
1288:
1247:
1216:
1175:
1121:
1063:
1056:
1038:
989:
954:
945:|journal=
919:
893:
854:
811:
782:(6): 529–538.
759:
707:
655:
597:
566:(6): 555–562.
546:
497:
458:
456:
453:
452:
451:
446:
439:
436:
403:Main article:
400:
397:
356:spermiogenesis
336:Main article:
333:
330:
325:
322:
277:
274:
257:
254:
248:
245:
184:
181:
173:genital ridges
155:In the mouse,
152:
149:
143:
140:
135:
132:
127:
124:
118:
115:
113:
110:
104:
101:
76:
73:
56:
53:
15:
13:
10:
9:
6:
4:
3:
2:
3188:
3177:
3174:
3172:
3169:
3168:
3166:
3145:
3142:
3140:
3137:
3135:
3132:
3131:
3130:
3129:Lateral plate
3127:
3125:
3122:
3118:
3115:
3113:
3110:
3109:
3108:
3105:
3103:
3100:
3099:
3097:
3095:
3091:
3085:
3082:
3081:
3079:
3077:
3073:
3067:
3064:
3062:
3059:
3057:
3054:
3052:
3051:Neuroectoderm
3049:
3047:
3044:
3043:
3041:
3039:
3035:
3029:
3026:
3022:
3019:
3018:
3017:
3014:
3010:
3007:
3005:
3001:
2998:
2996:
2995:Primitive pit
2993:
2992:
2991:
2987:
2984:
2983:
2981:
2979:
2975:
2972:
2969:
2962:
2956:
2953:
2951:
2948:
2947:
2945:
2942:
2935:
2929:
2926:
2924:
2921:
2919:
2916:
2914:
2911:
2909:
2906:
2904:
2901:
2899:
2896:
2894:
2891:
2889:
2886:
2884:
2881:
2879:
2878:Fertilization
2876:
2875:
2873:
2869:
2864:
2857:
2852:
2850:
2845:
2843:
2838:
2837:
2834:
2824:
2820:
2815:
2810:
2806:
2802:
2798:
2794:
2790:
2783:
2781:
2777:
2772:
2768:
2763:
2758:
2754:
2750:
2747:(2): 385–96.
2746:
2742:
2738:
2731:
2728:
2723:
2719:
2714:
2709:
2705:
2701:
2697:
2693:
2689:
2682:
2679:
2674:
2670:
2665:
2660:
2655:
2650:
2646:
2642:
2638:
2634:
2630:
2623:
2620:
2615:
2611:
2606:
2601:
2596:
2591:
2587:
2583:
2579:
2572:
2570:
2566:
2561:
2557:
2552:
2547:
2543:
2539:
2535:
2528:
2525:
2520:
2516:
2511:
2506:
2502:
2498:
2494:
2487:
2485:
2483:
2481:
2479:
2477:
2473:
2462:
2460:9780521401081
2456:
2452:
2448:
2444:
2443:
2435:
2432:
2427:
2423:
2418:
2413:
2408:
2403:
2399:
2395:
2391:
2387:
2383:
2376:
2373:
2368:
2364:
2359:
2354:
2350:
2346:
2342:
2338:
2334:
2327:
2324:
2319:
2315:
2310:
2305:
2301:
2297:
2293:
2286:
2283:
2278:
2274:
2269:
2264:
2259:
2254:
2250:
2246:
2242:
2238:
2234:
2227:
2224:
2219:
2215:
2211:
2207:
2203:
2199:
2195:
2191:
2187:
2180:
2177:
2172:
2168:
2164:
2160:
2156:
2152:
2148:
2144:
2140:
2136:
2129:
2126:
2121:
2117:
2112:
2107:
2104:(4): 519–32.
2103:
2099:
2095:
2088:
2086:
2082:
2077:
2073:
2068:
2063:
2060:(3): 571–84.
2059:
2055:
2051:
2044:
2042:
2038:
2033:
2029:
2024:
2019:
2015:
2011:
2007:
2003:
1999:
1995:
1991:
1984:
1981:
1976:
1972:
1967:
1962:
1958:
1954:
1950:
1946:
1942:
1938:
1934:
1927:
1924:
1919:
1915:
1910:
1905:
1901:
1897:
1893:
1889:
1885:
1881:
1877:
1870:
1867:
1862:
1858:
1853:
1848:
1843:
1838:
1835:(1): 214–23.
1834:
1830:
1826:
1819:
1817:
1813:
1808:
1804:
1799:
1794:
1790:
1786:
1783:(8): 905–15.
1782:
1778:
1774:
1767:
1764:
1759:
1755:
1750:
1745:
1741:
1737:
1733:
1729:
1725:
1718:
1715:
1710:
1706:
1702:
1698:
1694:
1690:
1686:
1682:
1678:
1674:
1667:
1664:
1659:
1655:
1650:
1645:
1642:(4): 559–62.
1641:
1637:
1633:
1626:
1623:
1618:
1614:
1610:
1606:
1602:
1598:
1594:
1590:
1583:
1580:
1575:
1571:
1567:
1563:
1559:
1555:
1551:
1547:
1543:
1539:
1532:
1529:
1524:
1520:
1515:
1510:
1507:(5): 516–29.
1506:
1502:
1498:
1491:
1489:
1487:
1485:
1481:
1476:
1472:
1467:
1462:
1457:
1452:
1448:
1444:
1441:(3): e57428.
1440:
1436:
1432:
1425:
1422:
1417:
1413:
1408:
1403:
1400:(2): 363–71.
1399:
1395:
1391:
1384:
1381:
1376:
1372:
1368:
1364:
1360:
1359:10.1038/11932
1356:
1352:
1348:
1341:
1338:
1333:
1329:
1325:
1321:
1316:
1311:
1307:
1303:
1299:
1292:
1289:
1284:
1280:
1275:
1270:
1267:(2): 484–92.
1266:
1262:
1258:
1251:
1248:
1243:
1239:
1235:
1231:
1227:
1220:
1217:
1212:
1208:
1203:
1198:
1194:
1190:
1186:
1179:
1176:
1171:
1167:
1162:
1157:
1153:
1149:
1146:(4): 424–36.
1145:
1141:
1137:
1130:
1128:
1126:
1122:
1117:
1113:
1108:
1103:
1099:
1095:
1091:
1087:
1083:
1076:
1074:
1072:
1070:
1068:
1064:
1059:
1053:
1049:
1042:
1039:
1034:
1030:
1025:
1020:
1016:
1012:
1009:(4): 219–33.
1008:
1004:
1000:
993:
990:
985:
981:
977:
973:
969:
965:
958:
955:
950:
938:
930:
926:
922:
916:
912:
908:
904:
897:
894:
889:
885:
881:
877:
873:
869:
865:
858:
855:
850:
846:
842:
838:
834:
830:
827:(2): 135–46.
826:
822:
815:
812:
807:
803:
798:
793:
789:
785:
781:
777:
773:
766:
764:
760:
755:
751:
747:
743:
738:
733:
729:
725:
721:
714:
712:
708:
703:
699:
694:
689:
685:
681:
677:
673:
669:
662:
660:
656:
651:
647:
642:
637:
633:
629:
625:
621:
617:
610:
608:
606:
604:
602:
598:
593:
589:
584:
579:
574:
569:
565:
561:
557:
550:
547:
542:
538:
533:
528:
524:
520:
517:(7): 406–16.
516:
512:
508:
501:
498:
493:
489:
485:
481:
477:
473:
466:
464:
460:
454:
450:
447:
445:
442:
441:
437:
435:
433:
429:
424:
420:
416:
412:
406:
398:
396:
394:
390:
386:
382:
381:
375:
373:
372:somatic cells
369:
365:
361:
357:
353:
349:
348:spermatocytes
345:
344:spermatogonia
339:
331:
329:
323:
321:
319:
315:
311:
307:
303:
302:retinoic acid
299:
295:
294:Sertoli cells
291:
286:
283:
275:
273:
269:
267:
263:
255:
253:
246:
244:
242:
238:
234:
230:
226:
221:
218:
217:transcription
212:
209:
205:
201:
197:
195:
191:
182:
180:
178:
174:
170:
166:
162:
158:
150:
148:
141:
139:
133:
131:
125:
123:
116:
111:
109:
102:
100:
98:
94:
90:
85:
83:
74:
72:
70:
66:
62:
54:
52:
50:
46:
42:
38:
37:differentiate
34:
30:
26:
22:
3124:Intermediate
3066:Neural crest
3021:Gastrulation
2796:
2792:
2744:
2740:
2730:
2695:
2691:
2681:
2636:
2632:
2622:
2585:
2581:
2541:
2537:
2527:
2500:
2496:
2464:. Retrieved
2441:
2434:
2389:
2385:
2375:
2340:
2336:
2326:
2299:
2295:
2285:
2240:
2236:
2226:
2196:(5): 841–7.
2193:
2189:
2179:
2138:
2134:
2128:
2101:
2097:
2057:
2053:
1997:
1993:
1983:
1940:
1936:
1926:
1883:
1879:
1869:
1832:
1828:
1780:
1776:
1766:
1731:
1727:
1717:
1676:
1672:
1666:
1639:
1635:
1625:
1592:
1588:
1582:
1541:
1537:
1531:
1504:
1500:
1438:
1434:
1424:
1397:
1393:
1383:
1353:(4): 361–5.
1350:
1346:
1340:
1305:
1301:
1291:
1264:
1260:
1250:
1233:
1229:
1219:
1192:
1188:
1178:
1143:
1139:
1089:
1085:
1047:
1041:
1006:
1002:
992:
967:
963:
957:
902:
896:
874:(2): 521–8.
871:
867:
857:
824:
820:
814:
779:
775:
727:
723:
675:
671:
626:(1): 37–49.
623:
619:
563:
559:
549:
514:
510:
500:
475:
471:
408:
378:
376:
341:
327:
287:
279:
270:
259:
250:
241:pluripotency
222:
213:
198:
186:
154:
145:
137:
129:
120:
106:
86:
78:
58:
18:
3061:Neurulation
2986:Archenteron
2978:Germ layers
2928:Trophoblast
2337:Development
970:(1): 32–9.
868:Development
730:(1): 3–18.
432:DNA damages
360:spermatozoa
117:Fruit flies
3165:Categories
3117:Somitomere
3004:Blastopore
2968:Trilaminar
2918:Blastocyst
2913:Blastocoel
2908:Cavitation
2898:Blastomere
2692:Aging Cell
2466:2019-11-27
1852:1765/19931
1595:: 219–39.
1236:: 133–47.
455:References
428:DNA repair
380:Drosophila
352:spermatids
227:, Nanos3,
177:E-cadherin
93:nanos gene
82:pole cells
61:germ plasm
2950:Hypoblast
2941:Bilaminar
2503:(2): 46.
947:ignored (
937:cite book
478:: 37–43.
444:Germ cell
423:meiosis I
419:diplotene
405:Oogenesis
399:Oogenesis
318:connexins
314:cadherins
282:gonocytes
266:teratomas
126:Zebrafish
3107:Paraxial
3094:Mesoderm
3076:Endoderm
3038:Ectoderm
3016:Gastrula
2955:Epiblast
2893:Cleavage
2823:23153565
2799:(1): 6.
2771:24318536
2741:Genetics
2722:28000382
2614:24324457
2560:22964823
2519:23843237
2426:31754036
2367:24917499
2318:29257950
2277:16578442
2218:37453479
2120:21820164
2076:19410550
2032:23223451
1975:20595612
1918:18354397
1861:19776388
1807:23851488
1758:11940672
1701:15937476
1658:18295574
1609:16285859
1523:24331926
1475:23469192
1435:PLOS ONE
1416:16289026
1375:22195563
1367:10431240
1332:18854728
1324:10894154
1283:11401407
1211:12351174
1170:10049358
1116:23125014
1033:23349011
984:24333597
849:31896844
841:13138919
754:11341985
746:19790240
702:24240231
650:20027186
592:28867677
541:26122616
438:See also
395:errors.
368:mutation
262:EG cells
204:epiblast
165:endoderm
49:germline
2964:Week 3
2937:Week 2
2814:4434944
2762:3914612
2713:5334535
2673:9707592
2641:Bibcode
2605:3840353
2588:: 181.
2417:6925976
2394:Bibcode
2358:4050694
2268:1063969
2245:Bibcode
2210:1381289
2171:4315359
2163:1383830
2143:Bibcode
2023:3847602
2002:Bibcode
1994:Science
1966:3863715
1945:Bibcode
1937:Science
1909:3847605
1888:Bibcode
1798:3796875
1709:4399840
1681:Bibcode
1617:6347720
1574:4365020
1566:2154694
1546:Bibcode
1466:3587611
1443:Bibcode
1242:7310300
1107:3536339
1024:3633705
1003:Genesis
929:7835158
888:2133553
806:2438119
797:3896947
693:3841730
641:4521894
583:5735266
532:4698964
492:3868485
415:oocytes
411:oogonia
393:meiotic
306:meiosis
169:hindgut
151:Mammals
69:gametes
29:gametes
3112:Somite
2903:Morula
2888:Zygote
2871:Week 1
2821:
2811:
2769:
2759:
2720:
2710:
2671:
2661:
2612:
2602:
2558:
2517:
2457:
2424:
2414:
2365:
2355:
2316:
2275:
2265:
2216:
2208:
2169:
2161:
2135:Nature
2118:
2074:
2030:
2020:
1973:
1963:
1916:
1906:
1880:Nature
1859:
1805:
1795:
1756:
1749:133770
1746:
1707:
1699:
1673:Nature
1656:
1615:
1607:
1572:
1564:
1538:Nature
1521:
1473:
1463:
1414:
1373:
1365:
1330:
1322:
1281:
1240:
1209:
1168:
1161:316469
1158:
1114:
1104:
1054:
1031:
1021:
982:
927:
917:
886:
847:
839:
804:
794:
752:
744:
700:
690:
648:
638:
590:
580:
539:
529:
490:
208:Blimp1
23:, the
2664:21453
2214:S2CID
2167:S2CID
1705:S2CID
1613:S2CID
1570:S2CID
1371:S2CID
1328:S2CID
845:S2CID
750:S2CID
229:Nanog
142:Birds
134:Frogs
97:oskar
89:oskar
45:gonad
39:into
25:cells
2819:PMID
2767:PMID
2718:PMID
2669:PMID
2610:PMID
2556:PMID
2515:PMID
2455:ISBN
2422:PMID
2363:PMID
2314:PMID
2273:PMID
2206:PMID
2190:Cell
2159:PMID
2116:PMID
2098:Cell
2072:PMID
2054:Cell
2028:PMID
1971:PMID
1914:PMID
1857:PMID
1803:PMID
1754:PMID
1697:PMID
1654:PMID
1636:Cell
1605:PMID
1562:PMID
1519:PMID
1471:PMID
1412:PMID
1363:PMID
1320:PMID
1279:PMID
1238:PMID
1207:PMID
1166:PMID
1112:PMID
1052:ISBN
1029:PMID
980:PMID
949:help
925:PMID
915:ISBN
884:PMID
837:PMID
802:PMID
742:PMID
698:PMID
646:PMID
588:PMID
537:PMID
488:PMID
316:and
225:Sox2
2809:PMC
2801:doi
2757:PMC
2749:doi
2745:196
2708:PMC
2700:doi
2659:PMC
2649:doi
2600:PMC
2590:doi
2546:doi
2505:doi
2447:doi
2412:PMC
2402:doi
2390:116
2353:PMC
2345:doi
2341:141
2304:doi
2263:PMC
2253:doi
2198:doi
2151:doi
2139:359
2106:doi
2102:146
2062:doi
2058:137
2018:PMC
2010:doi
1998:339
1961:PMC
1953:doi
1941:329
1904:PMC
1896:doi
1884:452
1847:hdl
1837:doi
1793:PMC
1785:doi
1744:PMC
1736:doi
1689:doi
1677:436
1644:doi
1640:132
1597:doi
1554:doi
1542:343
1509:doi
1461:PMC
1451:doi
1402:doi
1398:288
1355:doi
1310:doi
1269:doi
1265:232
1197:doi
1193:118
1156:PMC
1148:doi
1102:PMC
1094:doi
1019:PMC
1011:doi
972:doi
968:321
907:doi
876:doi
872:110
829:doi
825:118
792:PMC
784:doi
732:doi
688:PMC
680:doi
636:PMC
628:doi
578:PMC
568:doi
527:PMC
519:doi
480:doi
421:of
377:In
298:Sry
290:Sry
190:BMP
19:In
3167::
2817:.
2807:.
2797:88
2795:.
2791:.
2779:^
2765:.
2755:.
2743:.
2739:.
2716:.
2706:.
2696:16
2694:.
2690:.
2667:.
2657:.
2647:.
2637:95
2635:.
2631:.
2608:.
2598:.
2584:.
2580:.
2568:^
2554:.
2540:.
2536:.
2513:.
2501:89
2499:.
2495:.
2475:^
2453:.
2420:.
2410:.
2400:.
2388:.
2384:.
2361:.
2351:.
2339:.
2335:.
2312:.
2300:43
2298:.
2294:.
2271:.
2261:.
2251:.
2241:40
2239:.
2235:.
2212:.
2204:.
2194:70
2192:.
2188:.
2165:.
2157:.
2149:.
2137:.
2114:.
2100:.
2096:.
2084:^
2070:.
2056:.
2052:.
2040:^
2026:.
2016:.
2008:.
1996:.
1992:.
1969:.
1959:.
1951:.
1939:.
1935:.
1912:.
1902:.
1894:.
1882:.
1878:.
1855:.
1845:.
1833:82
1831:.
1827:.
1815:^
1801:.
1791:.
1781:15
1779:.
1775:.
1752:.
1742:.
1732:22
1730:.
1726:.
1703:.
1695:.
1687:.
1675:.
1652:.
1638:.
1634:.
1611:.
1603:.
1593:39
1591:.
1568:.
1560:.
1552:.
1540:.
1517:.
1505:27
1503:.
1499:.
1483:^
1469:.
1459:.
1449:.
1437:.
1433:.
1410:.
1396:.
1392:.
1369:.
1361:.
1351:22
1349:.
1326:.
1318:.
1306:14
1304:.
1300:.
1277:.
1263:.
1259:.
1234:64
1232:.
1228:.
1205:.
1191:.
1187:.
1164:.
1154:.
1144:13
1142:.
1138:.
1124:^
1110:.
1100:.
1088:.
1084:.
1066:^
1027:.
1017:.
1007:51
1005:.
1001:.
978:.
966:.
941::
939:}}
935:{{
923:.
913:.
882:.
870:.
866:.
843:.
835:.
823:.
800:.
790:.
780:66
778:.
774:.
762:^
748:.
740:.
728:77
726:.
722:.
710:^
696:.
686:.
676:27
674:.
670:.
658:^
644:.
634:.
624:11
622:.
618:.
600:^
586:.
576:.
564:63
562:.
558:.
535:.
525:.
515:16
513:.
509:.
486:.
476:50
474:.
462:^
374:.
362:.
196:.
91:,
3002:/
2988:/
2970:)
2966:(
2943:)
2939:(
2855:e
2848:t
2841:v
2825:.
2803::
2773:.
2751::
2724:.
2702::
2675:.
2651::
2643::
2616:.
2592::
2586:4
2562:.
2548::
2542:7
2521:.
2507::
2469:.
2449::
2428:.
2404::
2396::
2369:.
2347::
2320:.
2306::
2279:.
2255::
2247::
2220:.
2200::
2173:.
2153::
2145::
2122:.
2108::
2078:.
2064::
2034:.
2012::
2004::
1977:.
1955::
1947::
1920:.
1898::
1890::
1863:.
1849::
1839::
1809:.
1787::
1760:.
1738::
1711:.
1691::
1683::
1660:.
1646::
1619:.
1599::
1576:.
1556::
1548::
1525:.
1511::
1477:.
1453::
1445::
1439:8
1418:.
1404::
1377:.
1357::
1334:.
1312::
1285:.
1271::
1244:.
1213:.
1199::
1172:.
1150::
1118:.
1096::
1090:4
1060:.
1035:.
1013::
986:.
974::
951:)
931:.
909::
890:.
878::
851:.
831::
808:.
786::
756:.
734::
704:.
682::
652:.
630::
594:.
570::
543:.
521::
494:.
482::
Text is available under the Creative Commons Attribution-ShareAlike License. Additional terms may apply.