Autism spectrum disorders (ASDs) include a variety of developmental brain disorders with clinical findings implicating the dysfunction of the left hemisphere. Here, we generate mice lacking one copy of Sh3rf2, which was detected in ASD patients, to determine whether Sh3rf2 is involved in brain development and whether mutation of SH3RF2 is causative for ASD and the mechanisms linking it to ASD traits. We find that mice with Sh3rf2 haploinsufficiency display significant deficits in social interaction and communication, as well as stereotyped or repetitive behaviors and hyperactivity and seizures. Disturbances in hippocampal dendritic spine development, aberrant composition of glutamatergic receptor subunits, and abnormal excitatory synaptic transmission were detected in heterozygous mutants. Remarkably, these defects are selectively unilateral. Our results support a notion that Sh3rf2 haploinsufficiency is a highly penetrant risk factor for ASD, with disease pathogenesis most likely resulting from deficits in synaptic function in the left hemisphere of the brain.

Plants coordinate their growth and developmental programs with various endogenous signals and environmental challenges. Phytochrome interacting factor 4 (PIF4) plays a critical positive role in thermoresponsive gene expression and hypocotyl growth in Arabidopsis, whereas early flowering 3 (ELF3) negatively regulates the activity of PIF4 at elevated temperatures. However, it is unknown how ELF3 activity is regulated at warm temperatures. Here, we report the identification of B-box 18 (BBX18) and BBX23 as important thermomorphogenesis regulators in Arabidopsis. BBX18 and BBX23 mutations result in reduced thermoresponsive hypocotyl elongation. In contrast, BBX18 overexpression promotes hypocotyl growth at elevated temperatures, which depends on either PIF4 or constitutive photomorphogenic 1 (COP1). BBX18 and BBX23 interact with ELF3 or COP1. Knocking out BBX18 and BBX23 increases ELF3 abundance under normal and warm temperature conditions. The expression of multiple thermoresponsive genes is impaired in both a PIF4 mutant and a BBX18/BBX23 double mutant. Thus, our findings reveal an important role of B-box proteins during thermomorphogenesis and provide insights into our understanding of how warm temperature signals regulate ELF3 activity and PIF4-dependent genes.

Glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) is a critical regulatory molecule in modulation of T cell immune responses. Here we report the mouse GITR (mGITR) and mGITR ligand (mGITRL) complex structure and find that the binding interface of mGITR and mGITRL is distinct from the typical tumor necrosis factor superfamily (TNFSF)/TNF receptor superfamily (TNFRSF) members. mGITR binds to its ligand with a single domain, whereas the binding interface on mGITRL is located on the side, which is distal from conserved binding sites of TNFSF molecules. Mutational analysis reveals that the binding interface of GITR/GITRL in humans is conserved with that in the mouse. Substitution of key interacting D93-I94-V95 (DIV) in mGITR with the corresponding K93-F94-S95 (KFS) in human GITR enables cross-recognition with human GITRL and cross-activation of receptor signaling. The findings of this study substantially expand our understanding of the interaction of TNFSF/TNFRSF superfamily molecules and can benefit the future design of biologics by targeting GITR/GITRL.

Recognizing familiar faces and learning new faces play an important role in social cognition. However, the underlying neural computational mechanisms remain unclear. Here, we record from single neurons in the human amygdala and hippocampus and find a greater neuronal representational distance between pairs of familiar faces than unfamiliar faces, suggesting that neural representations for familiar faces are more distinct. Representational distance increases with exposures to the same identity, suggesting that neural face representations are sharpened with learning and familiarization. Furthermore, representational distance is positively correlated with visual dissimilarity between faces, and exposure to visually similar faces increases representational distance, thus sharpening neural representations. Finally, we construct a computational model that demonstrates an increase in the representational distance of artificial units with training. Together, our results suggest that the neuronal population geometry, quantified by the representational distance, encodes face familiarity, similarity, and learning, forming the basis of face recognition and memory.

Mutation or disruption of the Shank/ProSAP family of genes is a high risk factor for autism spectrum disorders (ASDs) and intellectual disability. N-methyl-D-aspartate glutamate receptor (NMDAR) dysfunction contributes to the development of autism-like behaviors. However, the molecular mechanism of Shank-mediated NMDAR modulation is still not clear. Here, we show that the scaffold protein plenty of SH3s (POSH) directly interacts with two other scaffold proteins, PSD95 and SHANK2/3, at excitatory synapses. In POSH conditional knockout (cKO) mice, normal synaptic clustering of NMDAR/PSD-95/SHANK complex is disrupted, accompanied by abnormal dendritic spine development and glutamatergic transmission in hippocampal neurons. POSH cKO mice display profound autism-like behaviors, including impairments in social interactions, social communication, repetitive behaviors, and deficits in learning and memory. Thus, POSH clusters at the postsynaptic density (PSD) with PSD-95 and SHANK2/3 and plays important roles in the signaling mechanisms of the NMDAR/PSD-95/POSH/SHANK complex as well as in spine development and brain function.