Primordial germ cell migration

Primordial germ cells are among the first lineages that are established in development[1] and they are the precursors for gametes.[2] It is thought that the process of primordial germ cell migration itself has been conserved rather than the specific mechanisms within it, as chemoattraction and repulsion seem to have been borrowed from blood cells, neurones, and the mesoderm.[1] For most organisms, PGC migration starts in the posterior (back end) of the embryo.

This process is in most cases distinct from PGC proliferation, with the exception of mammals in which both processes occur at the same time. In most mammals, specification occurs first, followed by migration, and then the proliferation process begins in the gonads.[1] PGCs interact with a wide range of cell types as they move from the epiblast to the gonads.[1] The PGCs move passively (without the need for energy) with underlying somatic cells, cross epithelial barriers, and respond to cues from their environment during active migration.[3] An epithelium must be crossed in many species during germ cell migration, and changes in adhesion are observed in PGCs during their exit from the endoderm and during the initiation of active migration.[3] Active migration takes place as PGCs move towards the developing somatic gonad.[3] Effective migration requires cell elongation and polarity.[1] Environmental guidance cues are required for the PGCs to initiate and sustain their mobility.[3] Specific molecular pathways are activated to give PGCs motility.[2]

In Drosophila, the whole migration process has been estimated to take 10 hours.[4] It begins with the formation of PGCs; from dividing nuclei becoming encircled by cell membranes, occurring at the posterior pole of the embryo.[5] Division of the nuclei stops once they have a cell membrane.[3] PGCs’ transcription process is also thought to be actively subdued once formed.[3]

In Drosophila, PGC migration begins with passive movement along the dorsal side of the embryo, during gastrulation.[4] This is followed by more passive movement, due to the invagination of the posterior midgut primordium, which leads to the PGCs in the centre of the embryo, surrounded by epithelial cells that have been folded back on themselves.[4] There is then a split into two groups, left and right respectively, as they actively migrate laterally across the epithelium to exit the gut, facilitated by fibroblast growth factor (FGF) signalling and a repulsion-based mechanism using enzymes encoded by the Wunen gene.[3][4][6] This is followed by active movement dorsally along the basal side of the embryo.[4] Through directional migration - which requires multiple genes to work, one being the Columbus (clb) gene, which codes for Drosophila HMG CoA reductase - the germ cells move towards the somatic gonadal precursor cells and associate with them.[3][6] These two associated cell types then migrate together anteriorly, until they coalesce into the embryonic gonad at the future site of the mature gonad.[4]

In vertebrate development, the location where primordial germ cells are specified and the subsequent migratory paths that they take differs among species.[1]

PGCs are described as the dedicated cells in early embryonic development, responsible for reaching the developing gonad.[3][9] During their migration however, heterogeneity of cellular behaviour is observed due to change in cellular morphology from the time of specification to colonization.[3] By the end of PGC migration, around 5% of migratory cells remain outside the gonad and later undergo apoptosis.[1]

The apoptotic route during the migratory period is occurring via an intrinsic pathway; nonetheless, the elimination of PGCs can be unsuccessful and result in tumour formation known as teratomas, derivatives of the three germ layers.[1][10] Mutations in Pten, CyclinD1, Dmrt1 and Dnd1 oncogenes in mice resulted in testicular teratomas, and variants are related with the same tumours in humans.[1] Tumour formation (neoplasm) from foetal gonocytes suggests that they are incapable of maintaining proliferative arrest and resistance to further differentiation.[1]

Even so, the origin of these teratomas could be distinct from the PGCs failing in migration.[11] Extragonadal germ cell tumours (GCTs) evolve due to a lesion along the midline of the body, prior to the migratory PGCs movement through the hindgut and the medial mesentery to the gonads.[3] Therefore, human GCTs originate from early embryo stem cells and the germ line, and unlike most tumours they seldom have somatic mutations, but instead are driven by unsuccessful control of their developmental potential, resulting in their reprogramming.[3]