PMID- 38077069
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240412
DP  - 2023 Nov 30
TI  - Loss of Slc35a2 alters development of the mouse cerebral cortex.
LID - 2023.11.29.569243 [pii]
LID - 10.1101/2023.11.29.569243 [doi]
AB  - Brain somatic variants in SLC35A2 are associated with clinically drug-resistant 
      epilepsy and developmental brain malformations, including mild malformation of 
      cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE). 
      SLC35A2 encodes a uridine diphosphate galactose translocator that is essential 
      for protein glycosylation; however, the neurodevelopmental mechanisms by which 
      SLC35A2 disruption leads to clinical and histopathological features remain 
      unspecified. We hypothesized that focal knockout (KO) or knockdown (KD) of 
      Slc35a2 in the developing mouse cortex would disrupt cerebral cortical 
      development through altered neuronal migration and cause changes in network 
      excitability. We used in utero electroporation (IUE) to introduce CRISPR/Cas9 and 
      targeted guide RNAs or short-hairpin RNAs to achieve Slc35a2 KO or KD, 
      respectively, during early corticogenesis. Following Slc35a2 KO or KD, we 
      observed disrupted radial migration of transfected neurons evidenced by 
      heterotopic cells located in lower cortical layers and in the sub-cortical white 
      matter. Slc35a2 KO in neurons did not induce changes in oligodendrocyte number, 
      suggesting that the oligodendroglial hyperplasia observed in MOGHE originates 
      from distinct cell autonomous effects. Spontaneous seizures were not observed, 
      but intracranial EEG recordings after focal KO showed a reduced seizure threshold 
      following pentylenetetrazol injection. These results demonstrate that Slc35a2 KO 
      or KD in vivo disrupts corticogenesis through altered neuronal migration.
FAU - Elziny, Soad
AU  - Elziny S
AD  - Department of Neurology, University of Maryland School of Medicine, Baltimore, 
      MD, USA.
FAU - Sran, Sahibjot
AU  - Sran S
AD  - Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, 
      USA.
FAU - Yoon, Hyojung
AU  - Yoon H
AD  - Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, 
      USA.
FAU - Corrigan, Rachel R
AU  - Corrigan RR
AD  - Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, 
      USA.
FAU - Page, John
AU  - Page J
AD  - Department of Neurology, University of Maryland School of Medicine, Baltimore, 
      MD, USA.
FAU - Ringland, Amanda
AU  - Ringland A
AD  - Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, 
      USA.
FAU - Lanier, Anna
AU  - Lanier A
AD  - Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, 
      USA.
FAU - Lapidus, Sara
AU  - Lapidus S
AD  - Department of Neurology, University of Maryland School of Medicine, Baltimore, 
      MD, USA.
FAU - Foreman, James
AU  - Foreman J
AD  - Department of Neurology, University of Maryland School of Medicine, Baltimore, 
      MD, USA.
FAU - Heinzen, Erin L
AU  - Heinzen EL
AD  - Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of 
      Pharmacy and Department of Genetics, School of Medicine, University of North 
      Carolina at Chapel Hill, Chapel Hill, NC.
FAU - Iffland, Philip
AU  - Iffland P
AD  - Department of Neurology, University of Maryland School of Medicine, Baltimore, 
      MD, USA.
FAU - Crino, Peter B
AU  - Crino PB
AD  - Department of Neurology, University of Maryland School of Medicine, Baltimore, 
      MD, USA.
FAU - Bedrosian, Tracy A
AU  - Bedrosian TA
AD  - Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, 
      USA.
AD  - Department of Pediatrics, The Ohio State University College of Medicine, 
      Columbus, OH, USA.
LA  - eng
GR  - R01 NS094596/NS/NINDS NIH HHS/United States
GR  - R01 NS115017/NS/NINDS NIH HHS/United States
GR  - R01 NS129784/NS/NINDS NIH HHS/United States
PT  - Preprint
DEP - 20231130
PL  - United States
TA  - bioRxiv
JT  - bioRxiv : the preprint server for biology
JID - 101680187
PMC - PMC10705455
OTO - NOTNLM
OT  - CRISPR
OT  - cerebral cortex
OT  - cortical dysplasia
OT  - glycosylation
OT  - short-hairpin RNA
COIS- Competing Interest Statement The authors have no competing interests to declare.
EDAT- 2023/12/11 12:43
MHDA- 2023/12/11 12:44
PMCR- 2023/12/08
CRDT- 2023/12/11 06:24
PHST- 2023/12/11 12:43 [pubmed]
PHST- 2023/12/11 12:44 [medline]
PHST- 2023/12/11 06:24 [entrez]
PHST- 2023/12/08 00:00 [pmc-release]
AID - 2023.11.29.569243 [pii]
AID - 10.1101/2023.11.29.569243 [doi]
PST - epublish
SO  - bioRxiv [Preprint]. 2023 Nov 30:2023.11.29.569243. doi: 
      10.1101/2023.11.29.569243.