Trio and Kalirin as unique enactors of Rho/Rac spatiotemporal precision

Grubisha, Melanie; DeGiosio, Rebecca A.; Will, Z.P.; Sweet, Robert A.

doi:10.1016/j.cellsig.2022.110416

Cited by 8 publications

(8 citation statements)

References 84 publications

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“…Again, this lack of change in activity may reflect compensatory mechanisms that normalize Rac1 and RhoA signaling. Of the many GEFs and GAPs expressed in the brain, TRIO may regulate Rac1 and/or RhoA only within a precise spatiotemporal window or within a narrowly defined subcellular context (16, 38, 106, 107). Further studies measuring local Rac1 and RhoA activity, either in subcellular fractions or by using activity-based reporters in cells, may help to resolve where and when Trio might act to regulate Rac1/RhoA and possible compensatory responses in these Trio mutants.…”

Section: Discussionmentioning

confidence: 99%

“…TRIO is highly expressed in the developing mammalian brain (8)(9)(10)(11)(12), where it is crucial in neuronal migration and morphogenesis, axon guidance, dendritic arbor and spine formation, synaptogenesis, postsynaptic function, and ultimately neuronal circuits impacting cognitive function (13)(14)(15)(16)(17)(18)(19)(20)(21). Mice with complete or neuronal-specific knockout of Trio exhibit decreased survival and abnormal skeletal muscle and neural tissue disorganization in several brain regions (22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

“…TRIO encodes a large cytoskeletal regulatory protein with two guanine nucleotide exchange factor (GEF) domains for Rho family GTPases -GEF1 activates Rac1 and RhoG, while GEF2 activates RhoA (35)(36)(37). As a dual RhoGEF, TRIO integrates signals downstream of cell surface receptors and acts on GTPases to coordinate cytoskeletal rearrangements critical for proper neurodevelopment (16,28,(38)(39)(40)(41)(42)(43)(44). Interestingly, nonsense variants spread throughout TRIO are enriched in individuals with SCZ (34,45), whereas pathogenic missense TRIO variants in or surrounding the GEF1 domain are associated with ASD/ID (9,32,33).…”

Section: Introductionmentioning

confidence: 99%

“…within a precise spatiotemporal window or within a narrowly defined subcellular context(16,38,106,107). Further studies measuring local Rac1 and RhoA activity, either in subcellular fractions or by using activity-based reporters in cells, may help to resolve where and whenTrio might act to regulate Rac1/RhoA and possible compensatory responses in these Trio mutants.…”

mentioning

confidence: 99%

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Heterozygosity for neurodevelopmental disorder-associatedTRIOvariants yields distinct deficits in behavior, neuronal development, and synaptic transmission in mice

Ishchenko,

Jeng,

Feng

et al. 2024

Preprint

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Heterozygosity for rare genetic variants inTRIOis associated with neurodevelopmental disorders (NDDs) including schizophrenia (SCZ), autism spectrum disorder (ASD) and intellectual disability. TRIO uses its two guanine nucleotide exchange factor (GEF) domains to activate GTPases (GEF1: Rac1 and RhoG; GEF2: RhoA) that control neuronal migration, synapse development and function. It remains unclear whether and how discreteTRIOvariants differentially impact these neurodevelopmental events. Here, we elucidate how heterozygosity for NDD-associatedTriovariants –+/K1431M(ASD),+/K1918X(SCZ), and+/M2145T(bipolar disorder, BPD) – impact mouse behavior, brain development, and synapse structure and function. Heterozygosity for differentTriovariants impacts motor, social, and cognitive behaviors in distinct ways that align with clinical phenotypes in humans. ASD- and SCZ-linkedTriovariants differentially impact head and brain size with corresponding changes in dendritic arbors of motor cortex layer 5 pyramidal neurons (M1 L5 PNs). Although dendritic spine density and synaptic ultrastructure were only modestly altered in theTriovariant heterozygotes, we observe significant changes in synaptic function and plasticity including excitatory/inhibitory imbalance and long-term potentiation defects. We also identify distinct changes in glutamate synaptic release in+/K1431Mand+/M2145Tcortico-cortical synapses, associated with deficiencies in crucial presynaptic release regulators. WhileTRIO K1431Mhas impaired ability to promote GTP exchange on Rac1,+/K1431Mmice exhibit increased Rac1 activity, suggesting possible compensation by other GEFs. Our work reveals that discrete disease-associatedTriovariants yield overlapping but distinct NDD-associated phenotypes in mice and demonstrates, for the first time, an essential role for Trio in presynaptic glutamate release, underscoring the importance of studying the impact of variant heterozygosity in vivo.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Heterozygosity for neurodevelopmental disorder-associatedTRIOvariants yields distinct deficits in behavior, neuronal development, and synaptic transmission in mice

Ishchenko,

Jeng,

Feng

et al. 2024

Preprint

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“…Endogenous Rac1 activity levels can be detected using an Rac1 fluorescence resonance energy transfer (FRET) biosensor [ 27 ]. Genetically encoded FRET-based sensors afford the view of spatiotemporal modular precision of Rac1-GTP [ 28 ]. Glutathione S-transferase (GST) or green fluorescent protein (GFP)-labeled PAK (p21 activated kinase)-RBD (Rac-binding domain) is an effective probe for detecting active Rac1.…”

Section: Molecular Structure and Activity Regulation Of Rac1mentioning

confidence: 99%

Rac1: A Regulator of Cell Migration and a Potential Target for Cancer Therapy

Luo

et al. 2023

Molecules

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Cell migration is crucial for physiological and pathological processes such as morphogenesis, wound repair, immune response and cancer invasion/metastasis. There are many factors affecting cell migration, and the regulatory mechanisms are complex. Rac1 is a GTP-binding protein with small molecular weight belonging to the Rac subfamily of the Rho GTPase family. As a key molecule in regulating cell migration, Rac1 participates in signal transduction from the external cell to the actin cytoskeleton and promotes the establishment of cell polarity which plays an important role in cancer cell invasion/metastasis. In this review, we firstly introduce the molecular structure and activity regulation of Rac1, and then summarize the role of Rac1 in cancer invasion/metastasis and other physiological processes. We also discuss the regulatory mechanisms of Rac1 in cell migration and highlight it as a potential target in cancer therapy. Finally, the current state as well as the future challenges in this area are considered. Understanding the role and the regulatory mechanism of Rac1 in cell migration can provide fundamental insights into Rac1-related cancer progression and further help us to develop novel intervention strategies for cancer therapy in clinic.

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