Knockout of the intellectual disability-linked gene Hs6st2 in mice decreases heparan sulfate 6-O-sulfation, impairs dendritic spines of hippocampal neurons, and affects memory
© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissionsoup.com..
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 three HS 6-O-sulfotransferases (HS6STs). Notably, HS6ST2 is mainly expressed in the brain and HS6ST2 mutations are linked to brain disorders, but the underlying mechanisms remain poorly understood. To determine the role of Hs6st2 in the brain, we carried out a series of molecular and behavioral assessments on Hs6st2 knockout mice. We first carried out strong anion exchange-high performance liquid chromatography and found that knockout of Hs6st2 moderately decreases HS 6-O-sulfation levels in the brain. We then assessed body weights and found that Hs6st2 knockout mice exhibit increased body weight, which is associated with abnormal metabolic pathways. We also performed behavioral tests and found that Hs6st2 knockout mice showed memory deficits, which recapitulate patient clinical symptoms. To determine the molecular mechanisms underlying the memory deficits, we used RNA sequencing to examine transcriptomes in two memory-related brain regions, the hippocampus and cerebral cortex. We found that knockout of Hs6st2 impairs transcriptome in the hippocampus, but only mildly in the cerebral cortex. Furthermore, the transcriptome changes in the hippocampus are enriched in dendrite and synapse pathways. We also found that knockout of Hs6st2 decreases HS levels and impairs dendritic spines in hippocampal CA1 pyramidal neurons. Taken together, our study provides novel molecular and behavioral insights into the role of Hs6st2 in the brain, which facilitates a better understanding of HS6ST2 and HS-linked brain disorders.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:34 |
|---|---|
| Enthalten in: |
Glycobiology - 34(2024), 2 vom: 26. März |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Moon, Sohyun [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 28.03.2024 Date Revised 01.04.2024 published: Print Citation Status MEDLINE |
|---|
| doi: |
10.1093/glycob/cwad095 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM365071676 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM365071676 | ||
| 003 | DE-627 | ||
| 005 | 20240401232420.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1093/glycob/cwad095 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1359.xml |
| 035 | |a (DE-627)NLM365071676 | ||
| 035 | |a (NLM)38015989 | ||
| 035 | |a (PII)cwad095 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Moon, Sohyun |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Knockout of the intellectual disability-linked gene Hs6st2 in mice decreases heparan sulfate 6-O-sulfation, impairs dendritic spines of hippocampal neurons, and affects memory |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 28.03.2024 | ||
| 500 | |a Date Revised 01.04.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissionsoup.com. | ||
| 520 | |a 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 three HS 6-O-sulfotransferases (HS6STs). Notably, HS6ST2 is mainly expressed in the brain and HS6ST2 mutations are linked to brain disorders, but the underlying mechanisms remain poorly understood. To determine the role of Hs6st2 in the brain, we carried out a series of molecular and behavioral assessments on Hs6st2 knockout mice. We first carried out strong anion exchange-high performance liquid chromatography and found that knockout of Hs6st2 moderately decreases HS 6-O-sulfation levels in the brain. We then assessed body weights and found that Hs6st2 knockout mice exhibit increased body weight, which is associated with abnormal metabolic pathways. We also performed behavioral tests and found that Hs6st2 knockout mice showed memory deficits, which recapitulate patient clinical symptoms. To determine the molecular mechanisms underlying the memory deficits, we used RNA sequencing to examine transcriptomes in two memory-related brain regions, the hippocampus and cerebral cortex. We found that knockout of Hs6st2 impairs transcriptome in the hippocampus, but only mildly in the cerebral cortex. Furthermore, the transcriptome changes in the hippocampus are enriched in dendrite and synapse pathways. We also found that knockout of Hs6st2 decreases HS levels and impairs dendritic spines in hippocampal CA1 pyramidal neurons. Taken together, our study provides novel molecular and behavioral insights into the role of Hs6st2 in the brain, which facilitates a better understanding of HS6ST2 and HS-linked brain disorders | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Dendritic spine | |
| 650 | 4 | |a HS6ST2 | |
| 650 | 4 | |a heparan sulfate | |
| 650 | 4 | |a heparan sulfate 6-O-sulfation | |
| 650 | 4 | |a memory | |
| 650 | 7 | |a Heparitin Sulfate |2 NLM | |
| 650 | 7 | |a 9050-30-0 |2 NLM | |
| 650 | 7 | |a HS 6 |2 NLM | |
| 650 | 7 | |a 22625-23-6 |2 NLM | |
| 650 | 7 | |a HS6ST2 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.8.2.- |2 NLM | |
| 650 | 7 | |a Pralidoxime Compounds |2 NLM | |
| 650 | 7 | |a Sulfotransferases |2 NLM | |
| 650 | 7 | |a EC 2.8.2.- |2 NLM | |
| 700 | 1 | |a Lee, Hiu Ham |e verfasserin |4 aut | |
| 700 | 1 | |a Archer-Hartmann, Stephanie |e verfasserin |4 aut | |
| 700 | 1 | |a Nagai, Naoko |e verfasserin |4 aut | |
| 700 | 1 | |a Mubasher, Zainab |e verfasserin |4 aut | |
| 700 | 1 | |a Parappurath, Mahima |e verfasserin |4 aut | |
| 700 | 1 | |a Ahmed, Laiba |e verfasserin |4 aut | |
| 700 | 1 | |a Ramos, Raddy L |e verfasserin |4 aut | |
| 700 | 1 | |a Kimata, Koji |e verfasserin |4 aut | |
| 700 | 1 | |a Azadi, Parastoo |e verfasserin |4 aut | |
| 700 | 1 | |a Cai, Weikang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Jerry Yingtao |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Glycobiology |d 1990 |g 34(2024), 2 vom: 26. März |w (DE-627)NLM012612502 |x 1460-2423 |7 nnns |
| 773 | 1 | 8 | |g volume:34 |g year:2024 |g number:2 |g day:26 |g month:03 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1093/glycob/cwad095 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 34 |j 2024 |e 2 |b 26 |c 03 | ||