BioProject

Heparan sulfate (HS) is a linear polysaccharide that plays a key role in cellular signaling networks. More...

Heparan sulfate (HS) is a linear polysaccharide that plays a key role in cellular signaling networks. HS functions are regulated by its 6-O-sulfation, which is catalyzed by HS 6-O-sulfotransferases (HS6STs). Although mutations in HS6ST2 cause intellectual disability in human patients, the role and molecular mechanisms of HS6ST2 in the adult mammalian brain remain unknown. Here we found that the brain specifically expresses the long isoform of Hs6st2, which encodes a protein that retains the sulfotransferase domain and acquires a novel sub-structure. To determine the role of Hs6st2 in the brain, we carried out a series of behavioral and molecular assessments on the Hs6st2 knockout mice. We found that Hs6st2 knockout mice exhibit high body weight, hyperactivity, and memory-related deficits. To determine the molecular mechanisms underlying these deficits, we carried out strong anion exchange-high performance liquid chromatography and RNA sequencing. We found that knockout of Hs6st2 decreases HS 6-O-sulfation levels in the brain and impairs transcriptome in the hippocampus. We also found that the transcriptome changes are enriched in genes involved in ribosome and protein translation pathways, which are likely due to the downregulation of the fibroblast growth factor signaling. Together, our study demonstrates the role and molecular mechanisms of Hs6st2 in the adult mammalian brain, which provides new insights into the role of HS in brain health and disease. Overall design: In this study, we analyzed the splicing patterns of Hs6st2 in different mouse tissues and investigated the protein structures of the long and short Hs6st2 isoforms using machine learning-based predictions. We also used cryo-recovery approach to re-generate the Hs6st2 knockout mice (KO) and carried out a series of behavioral and molecular assessments, including behavioral tests, strong anion exchange-high performance liquid chromatography (SAX-HPLC), and RNA sequencing (RNA-seq). Less...