Nucleotide exchange factor RIC‐8 is indispensable in mammalian early development

Tõnissoo, Tambet; Lulla, Sirje; Meier, Riho; Saare, Merly; Ruisu, Katrin; Pooga, Margus; Karis, Alar

doi:10.1002/dvdy.22480

Cited by 35 publications

(33 citation statements)

References 57 publications

(74 reference statements)

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“…Experiments on the function of Ric8 in mammalian cells have suggested an implication in the regulation of olfactory signaling via Gαolf (47), Gq-mediated ERK activation (48), and G-proteinmediated neural function and embryogenesis (49,50). This illustrates the relevant functions of mammalian Ric-8 in the regulation of G-protein signaling and suggests a similar mechanism of Ric8-mediated excitation of Gα-protein signaling as described here for Dictyostelium.…”

Section: Ric8 Is Essential For Chemotaxis Toward Folate and Shallow Gsupporting

confidence: 54%

Dictyostelium Ric8 is a nonreceptor guanine exchange factor for heterotrimeric G proteins and is important for development and chemotaxis

Kataria

Keizer‐Gunnink

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Heterotrimeric G proteins couple external signals to the activation of intracellular signal transduction pathways. Agonist-stimulated guanine nucleotide exchange activity of G-protein-coupled receptors results in the exchange of G-protein-bound GDP to GTP and the dissociation and activation of the complex into Gα-GTP and a Gβγ dimer. In Dictyostelium, a basal chemotaxis pathway consisting of heterotrimeric and monomeric G proteins is sufficient for chemotaxis. Symmetry breaking and amplification of chemoattractant sensing occurs between heterotrimeric G protein signaling and Ras activation. In a pull-down screen coupled to mass spectrometry, with Gα proteins as bait, we have identified resistant to inhibitors of cholinesterase 8 (Ric8) as a nonreceptor guanine nucleotide exchange factor for Gα-protein. Ric8 is not essential for the initial activation of heterotrimeric G proteins or Ras by uniform chemoattractant; however, it amplifies Gα signaling, which is essential for Ras-mediated symmetry breaking during chemotaxis and development.

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Section: Ric8 Is Essential For Chemotaxis Toward Folate and Shallow Gsupporting

confidence: 54%

Dictyostelium Ric8 is a nonreceptor guanine exchange factor for heterotrimeric G proteins and is important for development and chemotaxis

Kataria

Keizer‐Gunnink

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Osteoblast differentiation involves downregulation of genes associated with active proliferation and upregulation of genes involved in establishing the osteoblastic lineage (38). The Ric-8B gene encodes a GEF that has been shown to modulate G protein-dependent signaling in mitotic cells and control cell division (26,44,49,52). We found that the Ric-8B gene is strongly expressed in several osteoblastic and preosteoblastic cells that are actively proliferating.…”

Section: Resultsmentioning

confidence: 86%

The Ric-8B Gene Is Highly Expressed in Proliferating Preosteoblastic Cells and Downregulated during Osteoblast Differentiation in a SWI/SNF- and C/EBPβ-Mediated Manner

Grandy

Sepúlveda

Aguilar

et al. 2011

Molecular and Cellular Biology

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The Ric-8 gene encodes a guanine exchange factor (GEF) that modulates G protein-mediated signaling, exhibiting a relevant role during regulation of cell division. In mammals, two Ric-8 homologues have been reported (Ric-8A and Ric-8B), and recent studies indicate equivalent roles for each protein. Here, we show that the Ric-8B gene is negatively regulated during osteoblast differentiation by the transcription factor C/EBP␤. Only the larger C/EBP␤ isoform (C/EBP␤-LAP*) downregulates Ric-8B gene promoter activity in osteoblastic cells. Accordingly, knockdown of C/EBP␤ expression by small intefering RNA in osteoblastic cells results in a significant increase of Ric-8B gene expression. Transient overexpression of Brg1 or Brm, the catalytic subunits of the SWI/SNF chromatin-remodeling complex, inhibits Ric-8B promoter activity. Also, the presence of inactive SWI/SNF complexes in osteoblastic cells results in increased endogenous Ric-8B transcription, indicating that SWI/SNF activity negatively regulates Ric-8B expression. During osteoblast differentiation, Ric-8B gene repression is accompanied by changes in nucleosome placement at the proximal Ric-8B gene promoter and reduced accessibility to regulatory sequences.

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“…1 I, J ). Since conventional mutations in ric-8a result in early embryonic lethality (Tõnissoo et al, 2006(Tõnissoo et al, , 2010, to determine the in vivo function of ric-8a, we used a conditional allele of ric-8a (to be published elsewhere), in which exons 2-4 are flanked by a pair of loxP sites. To delete ric-8a, we used an hGFAP-cre that targets neural progenitors as well as astroglia throughout the nervous system (Zhuo et al, 2001;Malatesta et al, 2003).…”

Section: Resultsmentioning

confidence: 99%

Ric-8a, a Guanine Nucleotide Exchange Factor for Heterotrimeric G Proteins, Regulates Bergmann Glia-Basement Membrane Adhesion during Cerebellar Foliation

Ma¹,

Kwon

Huang³

2012

J. Neurosci.

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The cerebellum consists of an intricate array of lobules that arises during the process of foliation. Foliation not only increases surface area, but may also facilitate organization of cerebellar neural circuitry. Defects in cerebellar foliation are associated with a number of diseases. Yet, little is known about how foliation, a process involving large-scale and simultaneous movement of several different cell types, is coordinated by cell-cell signaling at the molecular level. Here we show that Ric-8a, a guanine nucleotide exchange factor in the G-proteincoupled receptor pathway, is specifically required in Bergmann glia during cerebellar foliation. We find that ric-8a mutation in mice results in disorganized Bergmann glial scaffolding, defective granule cell migration, and disrupted Purkinje cell positioning. These abnormalities result from primary defects in Bergmann glia since mutations in granule cells do not show similar effects. They first arise during late embryogenesis, at the onset of foliation, when ric-8a mutant Bergmann glia fail to maintain adhesion to the basement membrane specifically at emerging fissures. This suggests that Ric-8a is essential for the enhanced Bergmann glia-basement membrane adhesion required for fissure formation. Indeed, we find that ric-8a-deficient cerebellar glia show decreased affinity for basement membrane components. We also find that weakening Bergmann glia-basement membrane interaction by ␤1 integrin deletion results in a similar phenotype. These results thus reveal a novel role of Ric-8a in modulating Bergmann glia-basement membrane adhesion during foliation, and provide new insights into the signaling pathways that coordinate cellular movement during cerebellar morphogenesis.

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Nucleotide exchange factor RIC‐8 is indispensable in mammalian early development

Cited by 35 publications

References 57 publications

Dictyostelium Ric8 is a nonreceptor guanine exchange factor for heterotrimeric G proteins and is important for development and chemotaxis

Dictyostelium Ric8 is a nonreceptor guanine exchange factor for heterotrimeric G proteins and is important for development and chemotaxis

The Ric-8B Gene Is Highly Expressed in Proliferating Preosteoblastic Cells and Downregulated during Osteoblast Differentiation in a SWI/SNF- and C/EBPβ-Mediated Manner

Ric-8a, a Guanine Nucleotide Exchange Factor for Heterotrimeric G Proteins, Regulates Bergmann Glia-Basement Membrane Adhesion during Cerebellar Foliation

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