Conditional Deletion of<i>Ric-8b</i>in Olfactory Sensory Neurons Leads to Olfactory Impairment

Machado, Cleiton F.; Nagai, Maíra H.; Lyra, Cassandra Santantonio de; Reis-Silva, Thiago Marinho; Xavier, André Machado; Glezer, Isaías; Felício, Luciano Freitas; Malnic, Bettina

doi:10.1523/jneurosci.0943-17.2017

Cited by 14 publications

(12 citation statements)

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“…Consistent with the role of a GEF, Ric-8B is able to amplify odorant receptor signaling or dopamine receptor signaling through Gαolf in cultured cells [2,[7][8][9]. Also, a series of studies indicate that Ric-8B regulates Gα protein abundance in the cells, and suggest that Ric-8B may serve as a chaperone that promotes Gα protein stability and the formation of functional G protein complexes [7,8,[10][11][12][13].…”

Section: Introductionmentioning

confidence: 69%

Depletion of Ric-8B leads to reduced mTORC2 activity

et al. 2020

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mTOR, a serine/threonine protein kinase that is involved in a series of critical cellular processes, can be found in two functionally distinct complexes, mTORC1 and mTORC2. In contrast to mTORC1, little is known about the mechanisms that regulate mTORC2. Here we show that mTORC2 activity is reduced in mice with a hypomorphic mutation of the Ric-8B gene. Ric-8B is a highly conserved protein that acts as a non-canonical guanine nucleotide exchange factor (GEF) for heterotrimeric Gαs/olf type subunits. We found that Ric-8B hypomorph embryos are smaller than their wild type littermates, fail to close the neural tube in the cephalic region and die during mid-embryogenesis. Comparative transcriptome analysis revealed that signaling pathways involving GPCRs and G proteins are dysregulated in the Ric-8B mutant embryos. Interestingly, this analysis also revealed an unexpected impairment of the mTOR signaling pathway. Phosphorylation of Akt at Ser473 is downregulated in the Ric-8B mutant embryos, indicating a decreased activity of mTORC2. Knockdown of the endogenous Ric-8B gene in cultured cell lines leads to reduced phosphorylation levels of Akt (Ser473), further supporting the involvement of Ric-8B in mTORC2 activity. Our results reveal a crucial role for Ric-8B in development and provide novel insights into the signals that regulate mTORC2.

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Section: Introductionmentioning

confidence: 69%

Depletion of Ric-8B leads to reduced mTORC2 activity

et al. 2020

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“…Gγ13 is a G protein γ subunit that was first isolated from murine taste bud cells 11 . It has been found in the OSNs in the MOE, interacting with Gαolf, Gβ1 to form the heterotrimeric G protein Gαolf/β1/γ13 and transduce olfactory signals 7 , 12 , 15 , 16 . In this study, we investigated its expression pattern over developmental stages and found that both Gγ13 and Gαolf are expressed in the MOE as early as E5, indicating that the olfactory sensation may function in early embryonic stages (Fig.…”

Section: Discussionmentioning

confidence: 99%

G protein γ subunit Gγ13 is essential for olfactory function and aggressive behavior in mice

Chen

et al. 2018

NeuroReport

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Most olfactory receptors in vertebrates are G protein-coupled receptors, whose activation by odorants initiates intracellular signaling cascades through heterotrimeric G proteins consisting of α, β, and γ subunits. Abolishment of the α subunits such as Gαolf in the main olfactory epithelium and Gαi2 and Gαo in the vomeronasal organ resulted in anosmia and/or impaired behavioral responses. In this study, we report that a G protein γ subunit, Gγ13, is expressed in a spatiotemporal manner similar to those of Gαolf and Gαi2 in the olfactory system and vomeronasal organ, respectively. In addition, Gγ13 was found in the glomeruli of the main olfactory bulb but was largely absent in the glomeruli of the accessory olfactory bulb. Using the Cre-loxP system, the Gγ13’s gene Gng13 was nullified in the mature olfactory sensory neurons and apical vomeronasal sensory neurons where the Cre recombinase was expressed under the promoter of the Omp gene for the olfactory marker protein. Immunohistochemistry indicated much reduced expression of Gγ13 in the apical vomeronasal epithelium of the mutant mice. Behavioral experiments showed that the frequency and duration of aggressive encounters in the male mutant mice were significantly lower than in WT male mice. Taken together, these data suggest that the Gγ13 subunit is a critical signaling component in both the main olfactory epithelium and apical vomeronasal epithelium, and it plays an essential role in odor-triggered social behaviors including male–male aggression.

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“…Consistent with the role of a GEF, Ric-8B is able to amplify odorant receptor signaling or dopamine receptor signaling through Gαolf in cultured cells [2,7–9]. Also, a series of studies indicate that Ric-8B regulates Gα protein abundance in the cells, and suggest that Ric-8B may serve as a chaperone that promotes Gα protein stability and the formation of functional G protein complexes [7,8,10–13].…”

Section: Introductionmentioning

confidence: 87%

Depletion of Ric-8B leads to reduced mTORC2 activity

Nagai

Gutiyama

Xavier

et al. 2019

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AbstractmTOR, a serine/threonine protein kinase that is involved in a series of critical cellular processes, can be found in two functionally distinct complexes, mTORC1 and mTORC2. In contrast to mTORC1, little is known about the mechanisms that regulate mTORC2. Here we show that mTORC2 activity is reduced in mice with a hypomorphic mutation of the Ric-8B gene. Ric-8B is a highly conserved protein that acts as a non-canonical guanine nucleotide exchange factor (GEF) for heterotrimeric Gαs/olf type subunits. We found that Ric-8B hypomorph embryos are smaller than their wild type littermates, fail to close the neural tube in the cephalic region and die during mid-embryogenesis. Comparative transcriptome analysis revealed that signaling pathways involving GPCRs and G proteins are dysregulated in the Ric-8B mutant embryos. Interestingly, this analysis also revealed an unexpected impairment of the mTOR signaling pathway.Phosphorylation of Akt at Ser 473 is downregulated in the Ric-8B mutant embryos, indicating a decreased activity of mTORC2. In contrast, phosphorylation of S6, a downstream target of mTORC1, is unaltered. Knockdown of the endogenous Ric-8B gene in HEK293T cells leads to reduced phosphorylation levels of Akt at Ser 473, but not of S6, further supporting the selective involvement of Ric-8B in mTORC2 activity. Our results reveal a crucial role for Ric-8B in development and provide novel insights into the signals that regulate mTORC2 activity.Author SummaryGene inactivation in mice can be used to identify genes that are involved in important biological processes and that may contribute to disease. By using this approach, we found that the Ric-8B gene is essential for embryogenesis and for the normal development of the nervous system. Ric-8B mutant mouse embryos are smaller than their wild type littermates and show neural tube defects at the cranial region. This approach also allowed us to identify the biological pathways that are involved in the observed phenotypes, the G protein and mTORC2 signaling pathways. mTORC2 plays particular important roles also in the adult brain, and has been implicated in neurological disorders. Ric-8B is highly conserved in mammals, including humans. Our mutant mice provide a model to study the complex molecular and cellular processes underlying the interplay between Ric-8B and mTORC2 in neuronal function.

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Conditional Deletion ofRic-8bin Olfactory Sensory Neurons Leads to Olfactory Impairment

Cited by 14 publications

References 59 publications

Depletion of Ric-8B leads to reduced mTORC2 activity

Depletion of Ric-8B leads to reduced mTORC2 activity

G protein γ subunit Gγ13 is essential for olfactory function and aggressive behavior in mice

Depletion of Ric-8B leads to reduced mTORC2 activity

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