Role of NOX-produced ROS in the activation of SHH signaling pathway during cerebellar development

• Grant number: 17/18765-4
• Support Opportunities: Regular Research Grants
• Start date: April 01, 2018
• End date: March 31, 2020
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Marimélia Aparecida Porcionatto
• Grantee: Marimélia Aparecida Porcionatto
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

The mutant mouse Nox3eqlb lacks motor coordination caused by excess proliferation of granule cell precursors and abnormal arborization of Purkinje cell dendrites. Granule cells are the major neuronal type in the cerebellum, and the Purkinje cells are the only neurons that send outputs from the cerebellum. Defects in the production, proliferation and/or maturation of those cells cause phenotypes of affected motor coordination, known as ataxias, as observed for Nox3eqlb. Cerebellar development starts during the embryonic phase and is completed in postnatal period with the proliferation of granule cell precursors induced by the morphogenic factor sonic hedgehog (SHH), produced and secreted by Purkinje cells. Superexpression of SHH pathway genes, especially transcription factors of the GLI family, is related to medulloblastoma formation, a cerebellar tumor which cell origin is still in debate. Our data using Nox3eqlb reveal that the mutation in NADPH oxidase 3 (NOX3) that we described causes increased production of reactive oxygen species (ROS) by granule cell precursors. Increased amount of ROS seems to be responsible for at least one of the phenotypic features of the mutant, the excessive proliferation of granule cell precursors. We showed that SHH signaling pathway is enhanced in Nox3eqlb cerebellum, as we found upregulation o Gli1-3, cyclin D1 and Akt1 expression, as all of them are target genes of SHH. In this project we aim to evaluate if NOX-produced ROS affects the production of SHH, as well as other proteins important ofr the control of proliferation and maturation of cerebellar neurons. Additionally, we will look for microRNAS (miRNAs) that are relevant for the control of proliferation and maturation, and which expression is altered in the mutant mouse. With this project, we hope to identify the relation between NOX-produced ROS in the control of proliferation of granule cell precursors by SHH, with implications to the understanding of normal and pathological development of the cerebellum, including the ataxias and tumors. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MAZZONETTO, P. C.; ARIZA, C. B.; OCANHA, S. G.; DE SOUZ, T. A.; KO, G. M.; MENCK, C. F. M.; MASSIRONI, S. M. G.; PORCIONATTO, M. A.. Mutation in NADPH oxidase 3 (NOX3) impairs SHH signaling and increases cerebellar neural stem/progenitor cell proliferation. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, v. 1865, n. 6, p. 1502-1515, JUN 1 2019. (18/05635-8, 14/19204-8, 12/25387-2, 17/18765-4)

CHIARANTIN, GABRIELLY M. D.; DELGADO-GARCIA, LINA M.; ZAMPRONI, LAURA N.; LIMA, MARCELO A.; NADER, HELENA B.; TERSARIOL, IVARNE L. S.; PORCIONATTO, MARIMELIA. Neuroprotective effect of heparin Trisulfated disaccharide on ischemic stroke. GLYCOCONJUGATE JOURNAL, v. 38, n. 1, JAN 2021. (15/03964-6, 11/00526-7, 17/18765-4)