Odorant receptors: mechanisms of gene expression and signal transduction

• Grant number: 16/24471-0
• Support Opportunities: Research Projects - Thematic Grants
• Start date: April 01, 2017
• End date: March 31, 2023
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Bettina Malnic
• Grantee: Bettina Malnic
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• City of the host institution: São Paulo
• Associated researchers: Fabio Papes ; Isaias Glezer ; Pedro Alexandre Favoretto Galante
• Associated scholarship(s): 18/11860-4 - Epigenetic mechanisms in the regulation of gene expression: the case of odorant receptors, BP.PD

Abstract

Odorants activate odorant receptors (ORs) that are present in the cilia of the olfactory sensory neurons. Odorant receptors are G protein coupled receptors (GPCRs) and belong to a large family composed of approximately 1000 genes in the mouse, and 400 genes in humans. In this project, we aim to analyze two different aspects related to the function of these receptors: (1) Each olfactory sensory neuron expresses one allele of a single gene out of the ~ 1000 OR genes (the so called 'one neuron one receptor rule'). Olfactory neurons show a singular nuclear architecture, which seems to be required for odorant receptor gene regulation. We plan to analyze the role played by specific histone marks (such as H3K27me3) and non-coding RNAs in the spatial organization of the odorant receptor genes in the nucleus. (2) During odorant signal transduction, odorant receptors couple to an olfactory specific Galpha protein, denominated Galphaolf. We have shown that Ric-8B acts as a GEF (GTP exchange factor) on Galphaolf in vitro. Analysis of knockout mice showed that the Ric-8B gene is essential for embryogenesis, and that knockout embryos show reduced mTOR function. We plan to investigate the molecular mechanisms involved in the regulation of mTOR function by Ric-8B. We have also produced a tissue (olfactory epithelium) specific knockout for Ric-8B. Recent experiments have shown that olfactory sensory neurons from these mice do not express the Galphaolf protein, and die more frequently. We plan now to examine the molecular mechanisms that lead to such a phenotype. (AU)

Scientific publications

(9)

(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)

MACHADO, CLEITON F.; NAGAI, MARIA H.; LYRA, CASSANDRA S.; REIS-SILVA, THIAGO M.; MACHADO, ANDRE M.; GLEZER, ISAIAS; FELICIO, LUCIANO F.; MALNIC, BETTINA. Conditional Deletion of Ric-8b in Olfactory Sensory Neurons Leads to Olfactory Impairment. JOURNAL OF NEUROSCIENCE, v. 37, n. 50, p. 12202-12213, DEC 13 2017. (16/24471-0, 14/15495-8, 12/24640-6)

SBRANA, MARIANA FERREIRA; FORNAZIERI, MARCO AURELIO; BRUNI-CARDOSO, ALEXANDRE; AVELINO-SILVA, I, VIVIAN; SCHECHTMAN, DEBORAH; VOEGELS, RICHARD LOUIS; MALNIC, BETTINA; GLEZER, ISAIAS; PINNA, FABIO DE REZENDE. Olfactory Dysfunction in Frontline Health Care Professionals During COVID-19 Pandemic in Brazil. FRONTIERS IN PHYSIOLOGY, v. 12, MAR 9 2021. (18/18633-3, 19/06982-6, 16/24471-0, 13/07937-8, 19/26767-2)

NAGAI, MAIRA H.; XAVIER, VICTOR P. S.; GUTIYAMA, LUCIANA M.; MACHADO, CLEITON F.; REIS, ALICE H.; DONNARD, ELISA R.; GALANTE, PEDRO A. F.; ABREU, JOSE G.; FESTUCCIA, WILLIAM T.; MALNIC, BETTINA. Depletion of Ric-8B leads to reduced mTORC2 activity. PLOS GENETICS, v. 16, n. 5, MAY 2020. (14/15495-8, 19/05166-0, 16/24471-0)

MALNIC, BETTINA; LEME SILVA, ARTUR GUAZZELLI; NAGAI, MAIRA H.. DNA methylation pattern of an odorant receptor gene. CHEMICAL SENSES, v. 44, n. 3, p. 2-pg., 2019-03-01. (16/24471-0, 12/15882-6)

NAKAHARA, THIAGO; CAMARGO, ANTONIO; FIRMINO, LUIZ; NETTO, PAULO; DO NASCIMENTO, JOAO; DONNARD, ELISA; GALANTE, PEDRO; CARAZZOLLE, MARCELO; MALNIC, BETTINA; PAPES, FABIO. Uncovering long non-coding RNAs in the olfactory sensory organs. CHEMICAL SENSES, v. 45, n. 2, p. 2-pg., 2020-02-01. (16/24471-0, 15/50371-0, 18/11860-4, 11/22611-6, 16/05379-6)

MACHADO, CLEITON F.; REIS-SILVA, THIAGO M.; LYRA, CASSANDRA S.; FELICIO, LUCIANO F.; MALNIC, BETTINA. Buried Food-seeking Test for the Assessment of Olfactory Detection in Mice. BIO-PROTOCOL, v. 8, n. 12, JUN 20 2018. (16/24471-0, 12/24640-6)

LEME SILVA, ARTUR GUAZZELLI; NAGAI, MAIRA HARUME; NAKAHARA, THIAGO SEIKE; MALNIC, BETTINA. Genetic Background Effects on the Expression of an Odorant Receptor Gene. FRONTIERS IN CELLULAR NEUROSCIENCE, v. 15, FEB 25 2021. (12/15882-6, 18/11860-4, 16/24471-0)

CAMARGO, ANTONIO P.; NAKAHARA, THIAGO S.; FIRMINO, LUIZ E. R.; NETTO, PAULO H. M.; DO NASCIMENTO, JOAO B. P.; DONNARD, ELISA R.; GALANTE, PEDRO A. F.; CARAZZOLLE, MARCELO F.; MALNIC, BETTINA; PAPES, FABIO. Uncovering the mouse olfactory long non-coding transcriptome with a novel machine-learning model. DNA Research, v. 26, n. 4, p. 365-378, AUG 2019. (11/22611-6, 16/24471-0, 18/11860-4, 16/05379-6, 13/08293-7, 15/50371-0)

CRISAFULLI, UMBERTO; XAVIER, ANDRE M.; DOS SANTOS, FABIANA B.; CAMBIAGHI, TAVANE D.; CHANG, SEO Y.; PORCIONATTO, MARIMELIA; CASTILHO, BEATRIZ A.; MALNIC, BETTINA; GLEZER, ISAIAS. Topical Dexamethasone Administration Impairs Protein Synthesis and Neuronal Regeneration in the Olfactory Epithelium. FRONTIERS IN MOLECULAR NEUROSCIENCE, v. 11, MAR 6 2018. (09/04437-9, 07/53732-8, 16/24471-0, 11/13134-0, 09/52047-5, 13/07937-8)