The catalytic activity and secretion of zebrafish RNases are essential for their in vivo function in motor neurons and vasculature

• Published in: Scientific reports 2019-02, Vol.9 (1), p.1107-1107, Article 1107
• Main Authors: Ferguson, Ross, Holloway, Daniel E., Chandrasekhar, Anand, Acharya, K. Ravi, Subramanian, Vasanta
• Format: Article
• Language: English
• Subjects: 14; 38; 38/1; 38/77; 631/136; 631/378; 64; 64/116; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Angiogenesis; Angiogenin; Animals; Blood Vessels - metabolism; Blood Vessels - physiology; Catalysis; Cell migration; Cell Movement; Danio rerio; Embryos; Humanities and Social Sciences; Humans; Metabolites; Motor neurons; Motor Neurons - metabolism; Motor Neurons - physiology; multidisciplinary; Mutation - genetics; Neurogenesis; Neurons, Efferent - physiology; Neuroprotection; Ribonuclease A; Ribonuclease, Pancreatic - genetics; Ribonuclease, Pancreatic - metabolism; Ribonucleases - genetics; Ribonucleases - metabolism; Science; Science (multidisciplinary); Secretion; Zebrafish; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-37140-2

Angiogenin ( hANG ), a member of the Ribonuclease A superfamily has angiogenic, neurotrophic and neuroprotective activities. Mutations in hANG have been found in patients with Amyotrophic lateral sclerosis (ALS). The zebrafish ( Danio rerio ) rnasel-1 , 2 and 3 are orthologues of hANG and of these only Rnasel-1 and Rnasel-2 have been shown to be angiogenic. Herein we show that NCI-65828, a potent and specific small molecule inhibitor of hANG inhibits Rnasel-1 to a similar extent. Treatment of early zebrafish embryos with NCI-65828, or with terrein, a fungal metabolite which prevents the secretion of hANG, resulted in spinal neuron aberrations as well defects in trunk vasculature. Our detailed expression analysis and inhibitor studies suggest that Rnasel-1 plays important roles in neuronal migration and pathfinding as well as in angiogenesis in zebrafish. Our studies suggest the usefulness of the zebrafish as a model to dissect the molecular consequences of the ANG ALS variants.