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Retinitis pigmentosa (RP), a retinal degenerative disease, is the leading cause of heritable blindness. Previously, we described that Arap1−/− mice develop a similar pattern of photoreceptor degeneration. Arap1 is an Arf-directed GTPase-activating protein shown to modulate actin cytoskeletal dynamics. Curiously, Arap1 expression was detected in Müller glia and retinal pigment epithelium (RPE), but not the photoreceptors themselves. In this study, we generated conditional knockout mice for Müller glia/RPE, Müller glia and RPE via targeting Rlbp1, Glast and Vmd2 promoters, respectively, to drive Cre recombinase expression to knock out Arap1. Vmd2-Cre Arap1tm1c/tm1c and Rlbp1-Cre Arap1tm1c/tm1c mice, but not Glast-Cre Arap1tm1c/tm1c mice, recapitulated the phenotype originally observed in germline Arap1−/− mice. Mass spectrometry analysis of human ARAP1 co-immunoprecipitation identified candidate binding partners of ARAP1, revealing potential interactants involved in phagocytosis, cytoskeletal composition, intracellular trafficking and endocytosis. Quantification of outer segment phagocytosis in vivo demonstrated a clear phagocytic defect in Arap1−/− mice compared to Arap1+/+ controls. We conclude that Arap1 expression in RPE is necessary for photoreceptor survival due to its indispensable function in RPE phagocytosis. This article has an associated First Person interview with the first author of the paper.

Study Objectives: Children with snoring and mild sleep-disordered breathing may be at increased risk for neurocognitive deficits despite few obstructive events. We hypothesized that actigraphy-based sleep duration and continuity associate with neurobehavioral functioning and explored whether these associations vary by demographic and socioeconomic factors. Methods: 298 children enrolled in the Pediatric Adenotonsillectomy Trial, ages 3 to 12.9 years, 47.3% from racial or ethnic minority groups, with habitual snoring and an apnea-hypopnea index < 3 were studied with actigraphy (mean 7.5 ± 1.4 days) and completed a computerized vigilance task (Go-No-Go) and a test of fine motor control (9-Hole Pegboard). Caregivers completed the Behavior Rating Inventory of Executive Function. Regression analyses evaluated associations between sleep exposures (24-hour and nocturnal sleep duration, sleep fragmentation index, sleep efficiency) with the Behavior Rating Inventory of Executive Function Global Executive Composite index, pegboard completion time (fine motor control), and vigilance (d prime on the Go-No-Go), adjusting for demographic factors and study design measures. Results: Longer sleep duration, higher sleep efficiency, and lower sleep fragmentation were associated with better executive function; each additional hour of sleep over 24 hours associated with more than a 3-point improvement in executive function ( P = .002). Longer nocturnal sleep ( P = .02) and less sleep fragmentation ( P = .001) were associated with better fine motor control. Stronger associations were observed for boys and children less than 6 years old. Conclusions: Sleep quantity and continuity are associated with neurocognitive functioning in children with mild sleep-disordered breathing, supporting efforts to target these sleep health parameters as part of interventions for reducing neurobehavioral morbidity. Clinical Trial Registration: Registry: ClinicalTrials.gov; Name: Pediatric Adenotonsillectomy for Snoring (PATS); URL: https://clinicaltrials.gov/ct2/show/NCT02562040 ; Identifier: NCT02562040. Citation: Robinson KA, Wei Z, Radcliffe J, et al. Associations of actigraphy measures of sleep duration and continuity with executive function, vigilance, and fine motor control in children with snoring and mild sleep-disordered breathing. J Clin Sleep Med . 2023;19(9):1595–1603.

Purpose: Arap1 is an Arf-directed GTPase-activating protein (GAP) shown to modulate actin cytoskeletal dynamics by regulating Arf and Rho family members. We have previously shown that Arap1-/- mice develop photoreceptor degeneration similar to the human condition retinitis pigmentosa (RP), corroborated by fundus examination, histopathology, and ERG analysis. However, Arap1 expression was not detected in photoreceptors, but in Muller Glia and retinal pigment epithelium (RPE), suggesting a non-cell-autonomous mechanism for degeneration. The aim of this study was to elucidate the role of retinal Arap1 in photoreceptor maintenance. Methods: Albino Arap1-/- mice were generated via breeding pigmented Arap1-/- mice onto a Tyr-/- C57BL/6J background. Conditional knockout (cKO) mice were generated for Muller Glia/RPE, Muller Glia, and RPE via targeting Cralbp, Glast, and Vmd2 promoters, respectively, to drive Cre recombinase expression to knock out Arap1. Mice were analyzed by fundus photography, optical coherence tomography (OCT), histology, and immunohistochemistry. Arap1 binding partners were assayed by affinity purification mass spectrometry. Results: Vmd2-Cre Arap1 tm1c/tm1c and Cralbp-Cre Arap1 tm1c/tm1c mice, but not Glast-Cre Arap1 tm1c/tm1c mice, recapitulated the photoreceptor degeneration phenotype originally observed in germline Arap1-/- mice. These findings were corroborated by fundus exam, OCT, and histological analysis. Mass spectrometry analysis of ARAP1 co-immunoprecipitation identified putative binding partners of ARAP1, revealing numerous interactants involved in phagocytosis, cytoskeletal composition, intracellular trafficking, and endocytosis. Quantification of rod outer segment (OS) phagocytosis in vivo demonstrated a clear phagocytic defect in Arap1-/- mice compared to Arap1+/+ littermate controls while cone phagocytosis was preserved. Conclusions: Arap1 expression, specifically in RPE, is necessary for photoreceptor survival due to its indispensable function in RPE phagocytosis. We propose a model in which Arap1 regulates G-protein function for nonmuscle myosin II targeting during phagocytosis. This novel role of Arap1 is important for further understanding of both the diversity of its functions and the complex molecular regulation of RPE phagocytosis. Competing Interest Statement The authors have declared no competing interest.

Oocyte quality control culls eggs with defects in meiosis. In mouse, oocyte death is triggered by defects in chromosome synapsis and recombination, which involve repair of programmed DNA double-strand breaks (DSBs) between homologous chromosomes. We show that RNF212, a SUMO ligase required for crossing over, also mediates oocyte quality control. Both physiological apoptosis and wholesale oocytes elimination in meiotic mutants require RNF212. RNF212 sensitizes cells to DSB-induced apoptosis within a narrow window when chromosomes desynapse during the transition into quiescence. Analysis of DNA damage during this transition implies that RNF212 impedes DSB repair. Consistently, RNF212 is required for HORMAD1, a negative regulator of inter-sister recombination, to associate with desynapsing chromosomes. We infer that oocytes impede repair of residual DSBs to retain a \"memory\" of meiotic defects that enables quality control processes. These results define the logic of oocyte quality control and suggest RNF212 variants may influence transmission of defective genomes.