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B. L. Bohnsack, A. Kahana; Igf Regulates Neural Crest and Mesoderm Interactions Necessary for Zebrafish Orbital Development and Extraocular Muscle Organization. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3489.
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IGF1 signaling is involved in the pathogenesis of thyroid eye disease (TED) and craniofacial morphogenesis (1,2). We hypothesized that IGF1 signaling regulates interactions among the developing eye, mesoderm and neural crest in orbital and extraocular muscle development.
Zebrafish IGF signaling is highly homologous to the human. To test the in vivo function of IGF1 signaling in the orbit, we utilized transgenic fish strains expressing green fluorescent protein (GFP) driven by neural crest (sox10::GFP or foxD3::GFP) or muscle (α-actin::GFP) specific promoters. Embryos were injected with morpholino anti-sense oligonucleotides at the 1-cell stage to knockdown the expression of IGF-related genes. Lives embryos were harvested and imaged at different time points for analysis of neural crest and EOM development.
Injection of morpholinos against igf1ra and/or igf1rb into sox10::GFP and α-actin::GFP embryos effectively down-regulated IGF signaling. We found that igf1rb, but not igf1ra, was critical for proper cranial neural crest and EOM morphogenesis. Specifically, the neural crest-derived facial structures including the jaw were exquisitely sensitive to partial knockdown of igf1rb, while EOM organization was only disrupted with higher concentrations of igf1rb morpholinos. IGF signaling is modified by binding proteins (igfbp) and due to its reported role in jaw development (3) we also investigated igfbp3. Igfbp3 was required for proper migration of the rostral wave of cranial neural crest and appeared to regulate early induction and later maintenance of expression of foxD3 in the jaw and orbital tissues. In addition, igfbp3 knockdown affected the caliber and organization of EOM.
We demonstrate that IGF signaling regulates orbital development and EOM organization in zebrafish. The role of IGF in orbital development may shed light on the pathogenesis of TED.
1. Smith TJ et al. Thyroid 2008; 18: 983-9882. Li Y et al. J Biol Chem 2005; 280: 3613-36203. Duan C et al. Gen Comp Endocrinol 2005; 142: 44-52
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