Phenotypic Landscape of Schizophrenia-Associated Genes Defines Candidates and Their Shared Functions

Thyme, Summer B.; Pieper, Lindsey M.; Li, Eric H.; Pandey, Shristi; Wang, Yiqun; Morris, Nathan S.; Sha, Carrie; Choi, Joo Won; Herrera, Kristian J.; Soucy, Edward R.; Zimmerman, Steve; Randlett, Owen; Greenwood, Joel; McCarroll, Steven A.; Schier, Alexander F.

doi:10.1016/j.cell.2019.01.048

Cited by 150 publications

(156 citation statements)

References 67 publications

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“…Habituation deficits have been repeatedly observed across diverse neuropsychiatric disorders including autism spectrum disorder, Parkinson's disease, and schizophrenia . Multiple recent studies suggest that habituation of response probability is most susceptible to mutation and environmental perturbation . This could explain both why habituation deficits are so prevalent in disease and why they are so detrimental.…”

Section: Implications For Understanding Habituation Deficits In Neuromentioning

confidence: 99%

Habituation Is More Than Learning to Ignore: Multiple Mechanisms Serve to Facilitate Shifts in Behavioral Strategy

McDiarmid

Rankin

2019

BioEssays

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Recent work indicates that there are distinct response habituation mechanisms that can be recruited by different stimulation rates and that can underlie different components (e.g., the duration or speed) of a single behavioral response. These findings raise the question: why is “the simplest form of learning” so complicated mechanistically? Beyond evolutionary selection for robustness of plasticity in learning to ignore, it is proposed in this article that multiple mechanisms of habituation have evolved to streamline shifts in ongoing behavioral strategy. Then, speculations are offered regarding the implications of this reconceptualization of habituation for approaching the analysis of mechanisms of more complex forms of learning and memory.

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Section: Implications For Understanding Habituation Deficits In Neuromentioning

confidence: 99%

Habituation Is More Than Learning to Ignore: Multiple Mechanisms Serve to Facilitate Shifts in Behavioral Strategy

McDiarmid

Rankin

2019

BioEssays

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“…A common approach is to mutate candidate genes in cultured cells or animal models. The zebrafish is an attractive in vivo model for genetic screens in neuroscience (Tang et al, 2020;Thyme et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

A simple and effective F0 knockout method for rapid screening of behaviour and other complex phenotypes

Kroll

Powell

Ghosh

et al. 2020

Preprint

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Hundreds of human genes are associated with neurological diseases, but translation into tractable biological mechanisms is lagging. Larval zebrafish are an attractive model to investigate genetic contributions to neurological diseases. However, current CRISPR-Cas9 methods are difficult to apply to large genetic screens studying behavioural phenotypes. To facilitate rapid genetic screening, we developed a simple sequencing-free tool to validate gRNAs and a highly effective CRISPR-Cas9 method capable of converting >90% of injected embryos directly into F0 biallelic knockouts.We demonstrate that F0 knockouts reliably recapitulate complex mutant phenotypes, such as altered molecular rhythms of the circadian clock, escape responses to irritants, and multi-parameter day-night locomotor behaviours. The technique is sufficiently robust to knockout multiple genes in the same animal, for example to create the transparent triple knockout crystal fish for imaging. Our F0 knockout method cuts the experimental time from gene to behavioural phenotype in zebrafish from months to one week.

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“…Moreover, knocking down GIGYF2 in combination with RQC components had a strong synergistic growth interaction in the absence of a reporter, suggesting that there is a continuous production of endogenous stalling substrates. Loss of GIGYF2 has been associated with neurodegenerative and neurodevelopmental phenotypes (28,29), similar to loss of RQC components (30). It is tempting to speculate that dysregulation of the GIGYF2/4EHP pathway increases the burden on the proteostasis network in neurons leading to cell stress and/or death.…”

mentioning

confidence: 99%

GIGYF2 and 4EHP Inhibit Translation Initiation of Defective Messenger RNAs to Assist Ribosome-Associated Quality Control

Hickey

Cogan

Replogle

et al. 2019

Preprint

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Ribosome-associated Quality Control (RQC) pathways protect cells from toxicity caused by incomplete protein products resulting from translation of damaged or problematic mRNAs.Extensive work in yeast has identified highly conserved mechanisms that lead to the degradation of the faulty mRNA and partially synthesized polypeptide. Here, we used CRISPR-Cas9-based screening to search for additional RQC strategies in mammals. We found that failed translation leads to specific silencing of translation initiation on that message. This negative feedback loop is mediated by two translation inhibitors, GIGYF2 and 4EHP, in part via the ribosome collision sensor ZNF598. Both model substrates and growth-based assays established that inhibition of additional rounds of translation acts in concert with known RQC pathways to prevent buildup of toxic proteins. Inability to block translation of faulty mRNAs, and subsequent accumulation of partially synthesized polypeptides, could explain the neurodevelopmental and neuropsychiatric disorders observed in mice and humans with compromised GIGYF2 function.

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Phenotypic Landscape of Schizophrenia-Associated Genes Defines Candidates and Their Shared Functions

Cited by 150 publications

References 67 publications

Habituation Is More Than Learning to Ignore: Multiple Mechanisms Serve to Facilitate Shifts in Behavioral Strategy

Habituation Is More Than Learning to Ignore: Multiple Mechanisms Serve to Facilitate Shifts in Behavioral Strategy

A simple and effective F0 knockout method for rapid screening of behaviour and other complex phenotypes

GIGYF2 and 4EHP Inhibit Translation Initiation of Defective Messenger RNAs to Assist Ribosome-Associated Quality Control

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