Eugene Butcher, Postdoctoral Faculty Sponsor
Effects of the Co-Administration of MK-801 and Clozapine MiRNA Expression Profiles in Rats.
Basic & clinical pharmacology & toxicology
MiRNAs are small, non-coding RNAs that can silence the expression of various target genes by binding their mRNAs and thus regulate a wide range of crucial bodily functions. However, the miRNA expression profile of schizophrenia after antipsychotic mediation is largely unknown. Non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonists such as MK-801 have provided useful animal models to investigate the effects of schizophrenia-like symptoms in rodent animals. Herein, the hippocampal miRNA expression profiles of Sprague-Dawley rats pretreated with MK-801 were examined after antipsychotic clozapine (CLO) treatment. Total hippocampal RNAs from three groups were subjected to next-generation sequencing (NGS), and bioinformatics analyses, including differential expression and enrichment analyses, were performed. Eight miRNAs were differentially expressed between the MK-801 and vehicle (VEH) control groups. Interestingly, 14 miRNAs were significantly differentially expressed between the CLO+MK-801 and MK-801 groups, among which rno-miR-184 was the most upregulated. Further analyses suggested that these miRNAs modulate target genes that are involved in endocytosis regulation, ubiquitin-mediated proteolysis, and actin cytoskeleton regulation and thus might play important roles in the pathogenesis of schizophrenia. Our results suggest that differentially expressed miRNAs play important roles in the complex pathophysiology of schizophrenia and subsequently impact brain functions.
View details for DOI 10.1111/bcpt.13576
View details for PubMedID 33656787
A CD22-Shp1 phosphatase axis controls integrin beta7 display and B cell function in mucosal immunity.
The integrin alpha4beta7 selectively regulates lymphocyte trafficking and adhesion in the gut and gut-associated lymphoid tissue (GALT). Here, we describe unexpected involvement of the tyrosine phosphatase Shp1 and the B cell lectin CD22 (Siglec-2) in the regulation of alpha4beta7 surface expression and gut immunity. Shp1 selectively inhibited beta7 endocytosis, enhancing surface alpha4beta7 display and lymphocyte homing to GALT. In B cells, CD22 associated in a sialic acid-dependent manner with integrin beta7 on the cell surface to target intracellular Shp1 to beta7. Shp1 restrained plasma membrane beta7 phosphorylation and inhibited beta7 endocytosis without affecting beta1 integrin. B cells with reduced Shp1 activity, lacking CD22 or expressing CD22 with mutated Shp1-binding or carbohydrate-binding domains displayed parallel reductions in surface alpha4beta7 and in homing to GALT. Consistent with the specialized role of alpha4beta7 in intestinal immunity, CD22 deficiency selectively inhibited intestinal antibody and pathogen responses.
View details for DOI 10.1038/s41590-021-00862-z
View details for PubMedID 33589816