Insulin-like growth factor receptor 1b is required for zebrafish primordial germ cell migration and survival

Abstract

Insulin-like growth factor (IGF) signaling is a critical regulator of somatic growth during fetal and adult development, primarily through its stimulatory effects on cell proliferation and survival. IGF signaling is also required for development of the reproductive system, although its precise role in this regard remains unclear. We have hypothesized that IGF signaling is required for embryonic germline development, which requires the specification and proliferation of primordial germ cells (PGCs) in an extragonadal location, followed by directed migration to the genital ridges. We tested this hypothesis using loss-of-function studies in the zebrafish embryo, which possesses two functional copies of the Type-1 IGF receptor gene (igf1ra, igf1rb). Knockdown of IGF1Rb by morpholino oligonucleotides (MO) results in mismigration and elimination of primordial germ cells (PGCs), resulting in fewer PGCs colonizing the genital ridges. In contrast, knockdown of IGF1Ra has no effect on PGC migration or number despite inducing widespread somatic cell apoptosis. Ablation of both receptors, using combined MO injections or overexpression of a dominant-negative IGF1R, yields embryos with a PGC-deficient phenotype similar to IGF1Rb knockdown. TUNEL analyses revealed that mismigrated PGCs in IGF1Rb-deficient embryos are eliminated by apoptosis; overexpression of an antiapoptotic gene (Bcl2l) rescues ectopic PGCs from apoptosis but fails to rescue migration defects. Lastly, we show that suppression of IGF signaling leads to quantitative changes in the expression of genes encoding CXCL-family chemokine ligands and receptors involved in PGC migration. Collectively, these data suggest a novel role for IGF signaling in early germline development, potentially via cross-talk with chemokine signaling pathways.

The role of microenvironment in testicular germ cell tumors

“…50 In humans, CXCR4 expression in the adult testes has been detected in germ cells, while Sertoli cells have been found cells in their gonads due to the disruption of proper PGC migration and the subsequent apoptosis induced in the ectopically located cells. 48 This effect of IGF-I on PGC migration seems to be mediated by alterations in the SDF-1/CXCR4 signaling axis, which plays a decisive role in guiding germ cell migration in Figure 2. Testicular germ cell tumor microenvironment.…”

Neuroendocrine regulation of somatic growth in fishes

“…The gonadal expression of igf-3 is not regulated by GH signals, but by estrogen and/or gonadotropin [116,119]. IGFR1b is essential for zebrafish primordial germ cell (PGCs) migration and survival [120]. However, estrogen can disrupt post-embryonic growth by reducing GH sensitivity, IGF production, and IGF sensitivity in rainbow trout juveniles [121].…”

The spermatogonial stem cell niche in testicular germ cell tumors

“…This factor has been reported to be involved in the development of the embryonic mouse testis, in the regulation of testosterone production, and in spermatogenesis (Froment et al, 2007). Interestingly, IGF-I has also been identified as a key regulator of the SDF-1/CXCR4 signalling pathway, whose function is necessary for the proper migration of PGC (Schlueter et al, 2007) and has been associated with the metastatic pattern of several carcinomas, including TGCTs. Indeed, TGCTs exhibit an outstanding conserved pattern of metastases to organs that express high levels of SDF-1, such as lymph nodes, lungs and bone; resembling patterns observed in other CXCR4 over-expressing cancers.…”