Abstract
Anosmin-1 is a secreted glycoprotein encoded by the ANOS1 gene, and its loss of function causes Kallmann syndrome (KS), which is characterized by anosmia and hypogonadism due to olfactory bulb (OB) dysfunction. However, the physiological function of anosmin-1 remains to be elucidated. In KS, disordered angiogenesis is observed in OB, resulting in its hypoplasia. In this study, we examined the involvement of anosmin-1 in angiogenic processes. Anosmin-1 was detected on the vessel-like structure in OB of chick embryos, and promoted the outgrowth of vascular sprouts as shown by assays of OB tissue culture. Cell migration, proliferation, and tube formation of endothelial cells were induced by treatment with anosmin-1 as well as vascular endothelial growth factor-A (VEGF-A), and further enhanced by treatment with both of them. We newly identified that anosmin-1 activated VEGF receptor-2 (VEGFR2) by binding directly to it, and its downstream signaling molecules, phospholipase Cγ1 (PLCγ1) and protein kinase C (PKC). These results suggest that anosmin-1 plays a key role in the angiogenesis of developing OB through the VEGFR2–PLCγ1–PKC axis by enhancing the VEGF function.
Highlights
Anosmin-1 is a secreted glycoprotein encoded by the ANOS1 gene, and its loss of function causes Kallmann syndrome (KS), which is characterized by anosmia and hypogonadism due to olfactory bulb (OB) dysfunction
In addition to previous reports describing that anosmin-1 regulates neuronal cell functions, such as migration, branching, and neurite outgrowth, through activation of FGFR130–32, we newly demonstrated in this study that the protein localized at the vessel-like structures in the inner area of chick OB and promoted angiogenesis
It has already been shown by another research group that anosmin-1 directly binds to another growth factor receptor, FGFR124, for the promotion of migration in neuroblast cells, this is the first study to reveal the interaction between anosmin-1 and vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2) and novel functions of anosmin-1 in the angiogenic activity
Summary
Anosmin-1 is a secreted glycoprotein encoded by the ANOS1 gene, and its loss of function causes Kallmann syndrome (KS), which is characterized by anosmia and hypogonadism due to olfactory bulb (OB) dysfunction. We found that anosmin-1 promoted migration, proliferation, and tube formation of vascular endothelial cells, resulting in increased angiogenesis in OB. In VEGFR2-knockdown cells, treatment with anosmin-1 as well as VEGF-A did not induce cell migratory activity, compared with scramble RNA-transfected control cells (Supplementary Fig. S3f).
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