Insulin-like growth factor signaling regulates zebrafish embryonic growth and development by promoting cell survival and cell cycle progression

Abstract

Although much is known about the global effects of insulin-like growth factor 1 receptor (IGF1R)-mediated signaling on fetal growth and the clinical manifestations resulting from IGF/IGF1R deficiencies, we have an incomplete understanding of the cellular actions of this essential pathway during vertebrate embryogenesis. In this study, we inhibited IGF1R signaling during zebrafish embryogenesis using antisense morpholino oligonucleotides or a dominant-negative IGF1R fusion protein. IGF1R inhibition resulted in reduced embryonic growth, arrested development and increased lethality. IGF1R-deficient embryos had significant defects in the retina, inner ear, motoneurons and heart. No patterning abnormalities, however, were found in the brain or other embryonic tissues. At the cellular level, IGF1R inhibition increased caspase 3 activity and induced neuronal apoptosis. Coinjection of antiapoptotic bcl2-like mRNA attenuated the elevated apoptosis and rescued the retinal and motoneuron defects, but not the developmental arrest. Subsequent cell cycle analysis indicated an increased percentage of cells in G1 and a decreased percentage in S phase in IGF1R-deficient embryos independent of apoptosis. These results provide novel insight into the cellular basis of IGF1R function and show that IGF1R signaling does not function as an anteriorizing signal but regulates embryonic growth and development by promoting cell survival and cell cycle progression.

Calcium deficiency-induced and TRP channel-regulated IGF1R-PI3K-Akt signaling regulates abnormal epithelial cell proliferation

“…These results suggest that low [Ca 2 þ ] has no effect on the MEK-Erk signaling and that the basal pErk activity is independent from the IGF1R. 21 Blockage of IGF1R-mediated signaling by BMS-754807 or NVP-AEW541 reduced the low [Ca 2 þ ]-induced increase in NaR cell density in 92 and 79% of the larvae examined (Figures 4d and e) and abolished the low [Ca 2 þ ]-induced increase in igfbp5a mRNA levels (Figure 4f). Addition of wortmannin or LY294002 reduced the low [Ca 2 þ ]-induced NaR cell proliferation in 100 and 73% of the fish examined, whereas U0126 or PD98059 had no effect (Figure 4g).…”

“…Cell cycle analysis was carried out using a FACS Calibur flow cytometer (BD Biosciences, Franklin Lakes, NJ, USA) as previously described. 21 Statistics. Differences among experimental groups were analyzed by one-way ANOVA followed by Tukey's multiple comparison test using GraphPad Prism 5 (GraphPad Software, La Jolla, CA, USA).…”

Directing traffic in neural cells: determinants of receptor tyrosine kinase localization and cellular responses

“…Finally, late endosomes fuse with the lysosomal compartment (Tjelle et al (Mason et al 2003;Zeger et al 2007); Neuronal development (Schlueter et al 2007) ErbB4…”

Pregnancy-associated Plasma Protein A (PAPP-A) Modulates the Early Developmental Rate in Zebrafish Independently of Its Proteolytic Activity

“…Igf-II or igf-Ir knockdown embryos similarly display developmental delays, but with onset well into the segmentation period (20,23). Thus, the papp-a knockdown phenotype is different from the igf-II and igf-Ir knockdown phenotypes, further substantiated by our finding that the papp-a knockdown phenotype can be rescued by mRNA encoding either wild-type zebrafish Papp-a or a proteolytically inactive variant.…”

“…Interestingly, the developmental delay, beginning between 4 and 8 h post-fertilization, occurs much earlier than the delays resulting from knockdown in zebrafish of igf-II or igf-Ir, which begin between 12 and 24 hpf and by 16 hpf, respectively (20,23,34). The delay resulting from papp-a knockdown is therefore different from the Igf-related delay.…”