Table 1.
Key genes affecting PGC specification and proliferation/survival
| Gene | Function | Expressiona | Loss-of-function phenotype in PGCs |
|---|---|---|---|
| PGC SPECIFICATION | |||
| Cytokines | |||
| Bmp4 | A BMP/GDF/MIS subfamily ligand of the TGF-β family | ICM, ExE from E5.5, ExM during gastrulation | No and reduced number of PGCs in homozygous and heterozygous mutants, respectively; loss of Blimp1 and Prdm14 expression in homozygous mutants; loss of Bmp4 in the ExM leading to abnormal PGC localization and survival (Lawson et al. 1999; Fujiwara et al. 2001; Yamaji et al. 2008; Ohinata et al. 2009) |
| Bmp8b | A BMP/GDF/MIS subfamily ligand of the TGF-β family | ExE from E5.5 | No and reduced number of PGCs in homozygous and heterozygous mutants, respectively (C57BL/6 background); severely impaired Blimp1 and Prdm14 expression in homozygous mutants (Ying et al. 2000; Ohinata et al. 2009) |
| Bmp2 | A BMP/GDF/MIS subfamily ligand of the TGF-β family | VE | Reduced numbers of PGCs both in the heterozygous and homozygous mutants (C57BL/6 background) (Ying and Zhao 2001) |
| Wnt3 | A secreted glycoprotein of the Wnt family | Posterior proximal epiblast and VE, primitive streak, mesodermal wing | Loss of Blimp1 and Prdm14 expression in homozygous mutants (Ohinata et al. 2009) |
| Signal transducers | |||
| Smad1 | A receptor Smad for the BMP/GDF/MIS subfamily | Ubiquitous | No PGCs in homozygous mutants; severely impaired Blimp1 and Prdm14 expression in homozygous mutants (Tremblay et al. 2001; Hayashi et al. 2002; Aubin et al. 2004; Yamaji et al. 2008; Ohinata et al. 2009) |
| Smad5 | A receptor Smad for the BMP/GDF/MIS subfamily | Ubiquitous | No and reduced number of PGCs in homozygous and heterozygous mutants, respectively (Chang and Matzuk 2001) |
| Smad4 | A common partner for all receptor Smads | Ubiquitous | Severely reduced number of PGCs in epiblast-specific Smad4 knockouts (Chu et al. 2004) |
| Smad2 | A receptor Smad for the TGF-β/Activin/Nodal subfamily | Ubiquitous | Abundant PGCs at E8.5 in surviving embryos; widespread Blimp1 expression in early gastrulating embryos (Ohinata et al. 2009) |
| FoxH1 | A winged-helix transcription factor | Ubiquitous | Widespread Blimp1 expression in early gastrulating embryos (Ohinata et al. 2009) |
| Receptors | |||
| Alk2 | A type I BMP receptor (serine/threonine kinase) | Primarily VE before gastrulation | No and reduced number of PGCs in homozygous and heterozygous mutants, respectively (de Sousa Lopes et al. 2004) |
| Transcription factors (TFs) | |||
| Blimp1 | A TF with PR domain and Zinc fingers | PGCs, VE, many other lineages | Impaired PGC specification; reduced number of PGCs in heterozygous mutants (Vincent et al. 2005; Ohinata et al. 2009) |
| Prdm14 | A TF with PR domain and zinc fingers | PGCs, ICM | Impaired PGC specification (Yamaji et al. 2008) |
| Tcfap2c | A basic helix–span–helix TF | All cells until the blastocyst stage, ExE, PGCs | Impaired PGC specification in epiblast-specific Tcfap2c knockouts (Weber et al. 2010) |
| Oct4 | A POU-homeobox domain TF | Ubiquitous in the embryo proper until E7.5, specific to germ cells thereafter | Impaired PGC specification; apoptosis of PGCs (Kehler et al. 2004; Okamura et al. 2008) |
| RNA-binding protein | |||
| Lin28 | An RNA-binding protein | Ubiquitous | Reduced number of PGCs by RNAi-mediated Lin28 knockdown (West et al. 2009) |
| Cell adhesion molecules | |||
| Cdh1 | A homophilic cell–cell adhesion molecule | Epiblast, PGCs, and their somatic neighbors | An inhibitory antibody blocking PGC specification (Okamura et al. 2003) |
| PGC PROLIFERATION/SURVIVAL | |||
| Cytokines | |||
| Scf | A short-chain helical cytokine | The migratory path of PGCs | Impaired proliferation/survival and migration of PGCs (McCoshen and McCallion 1975; Gu et al. 2009) |
| Cxcl12 | A chemokine ligand | Gonad and subjacent mesonephric tissue at E12.5, widespread in embryos | Impaired migration of PGCs (Ara et al. 2003; Molyneaux et al. 2003) |
| Fgf9 | An FGF family ligand | Specific to male gonads after E12.5 | Impaired survival of male PGCs after E11.5 (DiNapoli et al. 2006) |
| Bmp7 | A BMP/GDF/MIS subfamily ligand of the TGF-β family | Specific to male gonads after E12.5 | Impaired PGC proliferation during E10.5–E11.5 in males (Ross et al. 2007) |
| Wnt5a | A secreted glycoprotein of the Wnt family | Widespread, up-regulated in testicular interstitial cells after E13.5 | Impaired proliferation/survival and migration of PGCs (Chawengsaksophak et al. 2011; Laird et al. 2011) |
| Signal transducers | |||
| Pten | A lipid phosphatase | Ubiquitous | Bilateral testicular teratoma (Kimura et al. 2003) |
| Bax | A proapoptotic factor of the Bcl2 family | Ubiquitous | Enhanced PGC survival (Stallock et al. 2003; Runyan et al. 2006; Suzuki et al. 2008; Cook et al. 2009; Gu et al. 2009) |
| Receptors | |||
| Kit | A receptor tyrosine kinase | PGCs | Impaired proliferation/survival and migration of PGCs (Mintz and Russell 1957; Buehr et al. 1993) |
| Cxcr4 | A seven-transmembrane spanning G-protein-coupled receptor | PGCs | Impaired migration/survival of PGCs (Ara et al. 2003; Molyneaux et al. 2003) |
| Fgfr2-IIIb | A receptor tyrosine kinase | Widespread | Impaired PGC survival at E11.5 (Takeuchi et al. 2005) |
| Ror2 | A receptor tyrosine kinase | Widespread | Impaired proliferation/survival and migration of PGCs (Laird et al. 2011) |
| Transcription factors | |||
| Oct4 | A POU-homeobox domain TF | Ubiquitous in the embryo proper until E7.5, specific to germ cells thereafter | Impaired PGC specification; apoptosis of PGCs (Kehler et al. 2004; Okamura et al. 2008) |
| Nanog | A divergent homeodomain TF | Morula, ICM, epiblast, primitive streak, PGCs | Apoptosis of PGCs (Chambers et al. 2007; Yamaguchi et al. 2009) |
| Hif2α | A bHLH-PAS TF | Ubiquitous | Reduced number of PGCs at E8.5 and eventual loss of PGCs (Covello et al. 2006) |
| RNA-binding proteins | |||
| Nanos3 | An RNA-binding protein | PGCs | Reduced number of PGCs at E8.0 and eventual loss of PGCs (Tsuda et al. 2003; Suzuki et al. 2008) |
| Dnd1 | An RNA-binding protein | PGCs, widespread in embryos at E7.5 | Reduced number of PGCs at E8.0 and eventual loss of PGCs (Sakurai 1995; Youngren et al. 2005; Cook et al. 2009) |
| Tiar | An RNA-binding protein | Ubiquitous | Reduced number of PGCs in the genital ridges at E11.5 and eventual loss of PGCs (Beck et al. 1998) |
| Mvh | A DEAD-box RNA helicase | PGCs after E10.5 | Impaired male PGC proliferation after E11.5 (Tanaka et al. 2000) |
| Dicer | RNase | Ubiquitous | Impaired PGC proliferation (Hayashi et al. 2008) |
| miRNAs | |||
| Mir-290-295 | Posttranscriptional regulation of gene expression | ESCs, embryos before E6.5, PGCs | Impaired migration/survival of PGCs (Medeiros et al. 2011) |
| Cell adhesion molecules | |||
| Gja1 | A gap-junction protein | PGCs, widespread in embryos | Impaired colonization of PGCs (Juneja et al. 1999; Francis and Lo 2006) |
| Itgb1 | A β subunit of integrin complex | PGCs, widespread in embryos | Impaired migration of PGCs (Anderson et al. 1999) |
| Others | |||
| Hp1γ | Heterochromatin protein with binding to H3K9me | Ubiquitous | Reduced number of PGCs after E7.25 due to impaired cell cycle (Abe et al. 2011) |
| Mcm9 | A minichromosome maintenance helicase paralog | Ubiquitous | Impaired PGC proliferation (Hartford et al. 2011) |
| Ft locus | A region of mouse chromosome 8 bearing six genes | Detected in embryonic gonads | Impaired PGC proliferation (Kim et al. 2011) |
aTissue types: ESC, embryonic stem cell; ExE, extra-embryonic ectoderm; ExM, extra-embryonic mesoderm; ICM, inner cell mass; PGC, primordial germ cell; VE, visceral endoderm.