Proteins of the Homer1 immediate early gene family have been associated with synaptogenesis and synaptic plasticity suggesting broad behavioral consequences of loss of function. This study examined the behavior of male Homer1 knockout (KO) mice compared with wildtype (WT) and heterozygous mice using a battery of 10 behavioral tests probing sensory, motor, social, emotional and learning/memory functions. KO mice showed mild somatic growth retardation, poor motor coordination, enhanced sensory reactivity and learning deficits. Heterozygous mice showed increased aggression in social interactions with conspecifics. The distribution of mGluR5 and N-methyl-D-aspartate receptors (NMDA) receptors appeared to be unaltered in the hippocampus (HIP) of Homer1 KO mice. The results indicate an extensive range of disrupted behaviors that should contribute to the understanding of the Homer1 gene in brain development and behavior.

Neutrophils play essential anti-microbial and inflammatory roles in host defense, however, their activities require tight regulation as dysfunction often leads to detrimental inflammatory and autoimmune diseases. Here we show that the adhesion molecule GPR97 allosterically activates CD177-associated membrane proteinase 3 (mPR3), and in conjugation with several protein interaction partners leads to neutrophil activation in humans. Crystallographic and deletion analysis of the GPR97 extracellular region identified two independent mPR3-binding domains. Mechanistically, the efficient binding and activation of mPR3 by GPR97 requires the macromolecular CD177/GPR97/PAR2/CD16b complex and induces the activation of PAR2, a G protein-coupled receptor known for its function in inflammation. Triggering PAR2 by the upstream complex leads to strong inflammatory activation, prompting anti-microbial activities and endothelial dysfunction. The role of the complex in pathologic inflammation is underscored by the finding that both GPR97 and mPR3 are upregulated on the surface of disease-associated neutrophils. In summary, we identify a PAR2 activation mechanism that directs neutrophil activation, and thus inflammation. The PR3/CD177/GPR97/PAR2/CD16b protein complex, therefore, represents a potential therapeutic target for neutrophil-mediated inflammatory diseases.

FAM46A belongs to the FAM46 subfamily of the nucleotidyltransferase-fold superfamily and is predicted to be a non-canonical poly(A) polymerase. FAM46A has been linked to several human disorders including retinitis pigmentosa, bone abnormality, cancer, and obesity. However, its molecular and functional characteristics are largely unknown. We herein report that FAM46A is expressed in cells of the hematopoietic system and plays a role in hemin-induced hemoglobinization. FAM46A is a nucleocytoplasmic shuttle protein modified by Tyr-phosphorylation only in the cytosol, where it is closely associated with ER. On the other hand, it is located proximal to the chromatin regions of active transcription in the nucleus. FAM46A is a cell cycle-dependent poly-ubiquitinated short-lived protein degraded mostly by proteasome and its overexpression inhibits cell growth and promotes hemin-induced hemoglobinization in K562 cell. Site-directed mutagenesis experiments confirm the non-canonical poly(A) polymerase activity of FAM46A is essential for enhanced hemin-induced hemoglobinization. In summary, FAM46A is a novel poly(A) polymerase that functions as a critical intracellular modulator of hemoglobinization.