Abnormal Behavior and Cortical Connectivity Deficits in Mice Lacking Usp9x

Abstract

Genetic association studies have identified many factors associated with neurodevelopmental disorders such as autism spectrum disorder (ASD). However, the way these genes shape neuroanatomical structure and connectivity is poorly understood. Recent research has focused on proteins that act as points of convergence for multiple factors, as these may provide greater insight into understanding the biology of neurodevelopmental disorders. USP9X, a deubiquitylating enzyme that regulates the stability of many ASD-related proteins, is one such point of convergence. Loss of function variants in human USP9X lead to brain malformations, which manifest as a neurodevelopmental syndrome that frequently includes ASD, but the underlying structural and connectomic abnormalities giving rise to patient symptoms is unknown. Here, we analyzed forebrain-specific Usp9x knockout mice (Usp9x−/y) to address this knowledge gap. Usp9x−/y mice displayed abnormal communication and social interaction behaviors. Moreover, the absence of Usp9x culminated in reductions to the size of multiple brain regions. Diffusion tensor magnetic resonance imaging revealed deficits in all three major forebrain commissures, as well as long-range hypoconnectivity between cortical and subcortical regions. These data identify USP9X as a key regulator of brain formation and function, and provide insights into the neurodevelopmental syndrome arising as a consequence of USP9X mutations in patients.

WWC1/2 regulate spinogenesis and cognition in mice by stabilizing AMOT

“…WWC1 is widely expressed in multiple brain regions, particularly in the hippocampus and cortex [ 53 ]. Nevertheless, it is unclear whether WWC2, USP9X, and Motins share similar expressions and functions in the nervous system, although abundant mRNA levels of these genes are detected in brain cells (Allen brain atlas) [ 37 , 54 , 55 ]. Western blot analysis revealed that WWC1/2 (no Wwc3 gene in mice), USP9X, and AMOT were ubiquitously expressed in the mouse brain, with relatively higher expression in cortex and hippocampus, regions highly related to memory function (Fig.…”

Polycomb repressive complex 2 is critical for mouse cortical glutamatergic neuron development

“…Eed fl/fl mice ( Yaghmaeian et al. 2018 ) were crossed with mice which expressed a codon-improved Cre recombinase gene under control of the Emx1 promotor ( Emx1 -iCre positive mice) ( Kasherman et al. 2021 ).…”

“…Vibratome-cut sections (50 μm thick) were mounted on SuperFrost Plus microscope slides (Menzel-Glasser, ThermoFisher Scientific) and air dried. Hematoxylin staining was performed using standard protocols as previously described ( Kasherman et al. 2021 ).…”

“…Antigen retrieval was performed with a decloaking chamber NxGen (Biocare Medical), at 95 °C for 15 min in citrate buffer. Immunofluorescent staining was performed as described previously ( Kasherman et al. 2021 ); details on the primary and secondary antibodies used are provided in the supplementary methods.…”

Comparison of Serum Usp9x and TGF-ß Levels in Children With Asd Spectrum Disorders With Healthy Controls

“…The underlying structural and link abnormalities in USP9X knockout mice (USP9x-/y) were analyzed in an up-to-date study with USP9X knockout mice (USP9x-/y). Although it is known that loss of function in the human USP9X can cause neurodevelopmental syndrome, including the OSB, the underlying structural and link abnormalities were analyzed in an up-to-date study with USP9X knockout mice (USP9x-Usp9x-/y mice exhibited aberrant communication and social interaction behavior, and the lack of Usp9x led in brain shrinkage in various areas (Kasherman et al 2021).…”