Molecular, physiological and behavioral characterization of the heterozygous Df[h15q13]/+ mouse model associated with the human 15q13.3 microdeletion syndrome

Rees, Katherine A.; Halawa, Amal A.; Consuegra-Garcia, Daisy; Golub, Victoria M.; Clossen, Bryan L.; Tan, Alexandra M.; Montgomery, Karienn S.; Reddy, Doodipala Samba; Griffith, William H.; Winzer‐Serhan, Ursula H.

doi:10.1016/j.brainres.2020.147024

Cited by 8 publications

(6 citation statements)

References 93 publications

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“…Individuals are typically heterozygous for the 15q13.3 microdeletion, which encompasses seven protein-coding genes, one microRNA, and two putative pseudogenes 22 . Mouse models of the 15q13.3 deletion display cortical dysfunction, behavioral abnormalities, and epilepsy, which are consistent with a developmental etiology [23][24][25][26][27] . Cortical excitatory and inhibitory neurons have both been implicated 26,[28][29][30] , but how dysfunction of either of these cell types occurs at the molecular level is not understood.…”

Section: Introductionmentioning

confidence: 60%

Impaired OTUD7A-dependent Ankyrin regulation mediates neuronal dysfunction in mouse and human models of the 15q13.3 microdeletion syndrome

Unda

Chalil

Yoon

et al. 2022

Preprint

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Copy number variations (CNV) are associated with psychiatric and neurodevelopmental disorders (NDDs), and most, including the recurrent 15q13.3 microdeletion disorder, have unknown disease mechanisms. We used a heterozygous 15q13.3 microdeletion mouse model and patient iPSC-derived neurons to reveal developmental defects in neuronal maturation and network activity. To identify the underlying molecular dysfunction, we developed a neuron-specific proximity-labeling proteomics (BioID2) pipeline, combined with patient mutations, to target the 15q13.3 CNV genetic driver OTUD7A. OTUD7A is an emerging independent NDD risk gene with no known function in the brain, but has putative deubiquitinase (DUB) function. The OTUD7A protein-protein interaction (PPI) network revealed interactions with synaptic, axonal, and cytoskeletal proteins and was enriched for known ASD and epilepsy risk genes. The interactions between OTUD7A and the NDD risk genes Ankyrin-G (Ank3) and Ankyrin-B (Ank2) were disrupted by an epilepsy-associated OTUD7A L233F variant. Further investigation of Ankyrin-G in mouse and human 15q13.3 microdeletion and OTUD7AL233F/L233F models revealed protein instability, increased polyubiquitination, and decreased levels in the axon initial segment (AIS), while structured illumination microscopy identified reduced Ankyrin-G nanodomains in dendritic spines. Functional analysis of human 15q13.3 microdeletion and OTUD7AL233F/L233F models revealed shared and distinct impairments to axonal growth and intrinsic excitability. Importantly, restoring OTUD7A or Ankyrin-G expression in 15q13.3 microdeletion neurons led to a reversal of abnormalities. These data reveal a critical OTUD7A-Ankyrin pathway in neuronal development, which is impaired in the 15q13.3 microdeletion syndrome, leading to neuronal dysfunction. Further, our study highlights the utility of targeting CNV genes using cell-type specific proteomics to identify shared and unexplored disease mechanisms across NDDs.

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Section: Introductionmentioning

confidence: 60%

Impaired OTUD7A-dependent Ankyrin regulation mediates neuronal dysfunction in mouse and human models of the 15q13.3 microdeletion syndrome

Unda

Chalil

Yoon

et al. 2022

Preprint

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“…The protocol consists of habituation, acquisition training (learning) and probe ( Figure 1B ; Rees et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

“…Multiple variables can be assessed during this task for cognitive (learning and memory of spatial-dependent navigation) and non-cognitive behaviors (speed, mobility). Distance and latency have been often used to demonstrate proficiency in finding the escape (Pitts, 2018 ; Rees et al, 2020 ). Quantification of latency may show level of efficiency to find the goal, but this variable is affected by age-dependent speed differences (Bizon et al, 2009 ).…”

Section: Introductionmentioning

confidence: 99%

Development of an age-dependent cognitive index: relationship between impaired learning and disturbances in circadian timekeeping

Souza

Powell

Allen

et al. 2022

Front. Aging Neurosci.

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Preclinical quantitative models of cognitive performance are necessary for translation from basic research to clinical studies. In rodents, non-cognitive factors are a potential influence on testing outcome and high variability in behavior requires multiple time point testing for better assessment of performance in more sophisticated tests. Thus, these models have limited translational value as most human cognitive tests characterize cognition using single digit scales to distinguish between impaired and unimpaired function. To address these limitations, we developed a cognitive index for learning based on previously described scores for strategies used by mice to escape the Barnes maze. We compared the cognitive index and circadian patterns of light-dark entrainment in young (4–6 months), middle-aged (13–14 months), and aged (18–24 months) mice as cognitive changes during aging are often accompanied by pronounced changes in sleep-wake cycle. Following continuous analysis of circadian wheel-running activity (30–40 days), the same cohorts of mice were tested in the Barnes maze. Aged mice showed significant deficits in the learning and memory portions of the Barnes maze relative to young and middle-aged animals, and the cognitive index was positively correlated to the memory portion of the task (probe) in all groups. Significant age-related alterations in circadian entrainment of the activity rhythm were observed in the middle-aged and aged cohorts. In middle-aged mice, the delayed phase angle of entrainment and increased variability in the daily onsets of activity preceded learning and memory deficits observed in aged animals. Interestingly, learning-impaired mice were distinguished by a positive relationship between the extent of Barnes-related cognitive impairment and variability in daily onsets of circadian activity. While it is unclear whether changes in the sleep-wake cycle or other circadian rhythms play a role in cognitive impairment during aging, our results suggest that circadian rhythm perturbations or misalignment may nevertheless provide an early predictor of age-related cognitive decline.

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“…[22]. Mouse models of the 15q13.3 deletion display cortical dysfunction, behavioral abnormalities, and epilepsy, which are consistent with a developmental etiology [23][24][25][26][27]. Cortical excitatory and inhibitory neurons have both been implicated [26,[28][29][30], but how dysfunction of either of these cell types occurs at the molecular level is not understood.…”

Section: Introductionmentioning

confidence: 99%

“…Individuals are typically heterozygous for the 15q13.3 microdeletion, which encompasses seven protein-coding genes, one microRNA, and two putative pseudogenes ( ARHGAP11BI [MIM: 616310], LOC100288637 , FAN1 [MIM: 613534], MTMR10 , TRPM1 [MIM: 603576], LOC283710 , microRNA-211, KLF13 [MIM: 605328], OTUD7A [MIM: 612024], and CHRNA7 [MIM: 118511]) [ 22 ]. Mouse models of the 15q13.3 deletion display cortical dysfunction, behavioral abnormalities, and epilepsy, which are consistent with a developmental etiology [ 23 – 27 ]. Cortical excitatory and inhibitory neurons have both been implicated [ 26 , 28 – 30 ], but how dysfunction of either of these cell types occurs at the molecular level is not understood.…”

Section: Introductionmentioning

confidence: 99%

Impaired OTUD7A-dependent Ankyrin regulation mediates neuronal dysfunction in mouse and human models of the 15q13.3 microdeletion syndrome

et al. 2023

View full text Add to dashboard Cite

Copy number variations (CNVs) are associated with psychiatric and neurodevelopmental disorders (NDDs), and most, including the recurrent 15q13.3 microdeletion disorder, have unknown disease mechanisms. We used a heterozygous 15q13.3 microdeletion mouse model and patient iPSC-derived neurons to reveal developmental defects in neuronal maturation and network activity. To identify the underlying molecular dysfunction, we developed a neuron-specific proximity-labeling proteomics (BioID2) pipeline, combined with patient mutations, to target the 15q13.3 CNV genetic driver OTUD7A. OTUD7A is an emerging independent NDD risk gene with no known function in the brain, but has putative deubiquitinase function. The OTUD7A protein–protein interaction network included synaptic, axonal, and cytoskeletal proteins and was enriched for ASD and epilepsy risk genes (Ank3, Ank2, SPTAN1, SPTBN1). The interactions between OTUD7A and Ankyrin-G (Ank3) and Ankyrin-B (Ank2) were disrupted by an epilepsy-associated OTUD7A L233F variant. Further investigation of Ankyrin-G in mouse and human 15q13.3 microdeletion and OTUD7AL233F/L233F models revealed protein instability, increased polyubiquitination, and decreased levels in the axon initial segment, while structured illumination microscopy identified reduced Ankyrin-G nanodomains in dendritic spines. Functional analysis of human 15q13.3 microdeletion and OTUD7AL233F/L233F models revealed shared and distinct impairments to axonal growth and intrinsic excitability. Importantly, restoring OTUD7A or Ankyrin-G expression in 15q13.3 microdeletion neurons led to a reversal of abnormalities. These data reveal a critical OTUD7A-Ankyrin pathway in neuronal development, which is impaired in the 15q13.3 microdeletion syndrome, leading to neuronal dysfunction. Furthermore, our study highlights the utility of targeting CNV genes using cell type-specific proteomics to identify shared and unexplored disease mechanisms across NDDs.

show abstract

Molecular, physiological and behavioral characterization of the heterozygous Df[h15q13]/+ mouse model associated with the human 15q13.3 microdeletion syndrome

Cited by 8 publications

References 93 publications

Impaired OTUD7A-dependent Ankyrin regulation mediates neuronal dysfunction in mouse and human models of the 15q13.3 microdeletion syndrome

Impaired OTUD7A-dependent Ankyrin regulation mediates neuronal dysfunction in mouse and human models of the 15q13.3 microdeletion syndrome

Development of an age-dependent cognitive index: relationship between impaired learning and disturbances in circadian timekeeping

Impaired OTUD7A-dependent Ankyrin regulation mediates neuronal dysfunction in mouse and human models of the 15q13.3 microdeletion syndrome

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