PMID- 37211968
OWN - NLM
STAT- MEDLINE
DCOM- 20230718
LR  - 20230719
IS  - 1460-2075 (Electronic)
IS  - 0261-4189 (Print)
IS  - 0261-4189 (Linking)
VI  - 42
IP  - 14
DP  - 2023 Jul 17
TI  - Phospholipid scramblase Xkr8 is required for developmental axon pruning via 
      phosphatidylserine exposure.
PG  - e111790
LID - 10.15252/embj.2022111790 [doi]
LID - e111790
AB  - The mature mammalian brain connectome emerges during development via the 
      extension and pruning of neuronal connections. Glial cells have been identified 
      as key players in the phagocytic elimination of neuronal synapses and 
      projections. Recently, phosphatidylserine has been identified as neuronal 
      "eat-me" signal that guides elimination of unnecessary input sources, but the 
      associated transduction systems involved in such pruning are yet to be described. 
      Here, we identified Xk-related protein 8 (Xkr8), a phospholipid scramblase, as a 
      key factor for the pruning of axons in the developing mammalian brain. We found 
      that mouse Xkr8 is highly expressed immediately after birth and required for 
      phosphatidylserine exposure in the hippocampus. Mice lacking Xkr8 showed excess 
      excitatory nerve terminals, increased density of cortico-cortical and 
      cortico-spinal projections, aberrant electrophysiological profiles of hippocampal 
      neurons, and global brain hyperconnectivity. These data identify phospholipid 
      scrambling by Xkr8 as a central process in the labeling and discrimination of 
      developing neuronal projections for pruning in the mammalian brain.
CI  - (c) 2023 The Authors. Published under the terms of the CC BY 4.0 license.
FAU - Neniskyte, Urte
AU  - Neniskyte U
AUID- ORCID: 0000-0001-7645-703X
AD  - VU LSC-EMBL Partnership for Genome Editing Technologies, Life Sciences Center, 
      Vilnius University, Vilnius, Lithuania.
AD  - Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, 
      Lithuania.
AD  - Epigenetics and Neurobiology Unit, European Molecular Biology Laboratory (EMBL), 
      Monterotondo, Italy.
FAU - Kuliesiute, Ugne
AU  - Kuliesiute U
AD  - VU LSC-EMBL Partnership for Genome Editing Technologies, Life Sciences Center, 
      Vilnius University, Vilnius, Lithuania.
AD  - Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, 
      Lithuania.
FAU - Vadisiute, Auguste
AU  - Vadisiute A
AUID- ORCID: 0000-0002-6722-7504
AD  - Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, 
      Lithuania.
AD  - Epigenetics and Neurobiology Unit, European Molecular Biology Laboratory (EMBL), 
      Monterotondo, Italy.
AD  - Department of Physiology and Pharmacology - Center for Research in Neurobiology, 
      Sapienza University, Rome, Italy.
FAU - Jevdokimenko, Kristina
AU  - Jevdokimenko K
AD  - Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, 
      Lithuania.
FAU - Coletta, Ludovico
AU  - Coletta L
AD  - Functional Neuroimaging Laboratory, Italian Institute of Technology (IIT), Center 
      for Neuroscience and Cognitive Systems @UNITN, Rovereto, Italy.
FAU - Deivasigamani, Senthilkumar
AU  - Deivasigamani S
AD  - Epigenetics and Neurobiology Unit, European Molecular Biology Laboratory (EMBL), 
      Monterotondo, Italy.
FAU - Pamedytyte, Daina
AU  - Pamedytyte D
AD  - VU LSC-EMBL Partnership for Genome Editing Technologies, Life Sciences Center, 
      Vilnius University, Vilnius, Lithuania.
AD  - Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, 
      Lithuania.
FAU - Daugelaviciene, Neringa
AU  - Daugelaviciene N
AD  - VU LSC-EMBL Partnership for Genome Editing Technologies, Life Sciences Center, 
      Vilnius University, Vilnius, Lithuania.
AD  - Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, 
      Lithuania.
FAU - Dabkeviciene, Daiva
AU  - Dabkeviciene D
AD  - VU LSC-EMBL Partnership for Genome Editing Technologies, Life Sciences Center, 
      Vilnius University, Vilnius, Lithuania.
FAU - Perlas, Emerald
AU  - Perlas E
AD  - Epigenetics and Neurobiology Unit, European Molecular Biology Laboratory (EMBL), 
      Monterotondo, Italy.
FAU - Bali, Aditya
AU  - Bali A
AUID- ORCID: 0000-0003-0804-3251
AD  - Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, 
      Lithuania.
FAU - Basilico, Bernadette
AU  - Basilico B
AD  - Department of Physiology and Pharmacology - Center for Research in Neurobiology, 
      Sapienza University, Rome, Italy.
FAU - Gozzi, Alessandro
AU  - Gozzi A
AD  - Functional Neuroimaging Laboratory, Italian Institute of Technology (IIT), Center 
      for Neuroscience and Cognitive Systems @UNITN, Rovereto, Italy.
FAU - Ragozzino, Davide
AU  - Ragozzino D
AUID- ORCID: 0000-0002-3290-7665
AD  - Department of Physiology and Pharmacology - Center for Research in Neurobiology, 
      Sapienza University, Rome, Italy.
FAU - Gross, Cornelius T
AU  - Gross CT
AUID- ORCID: 0000-0001-9129-1322
AD  - Epigenetics and Neurobiology Unit, European Molecular Biology Laboratory (EMBL), 
      Monterotondo, Italy.
LA  - eng
GR  - 802371/ERC_/European Research Council/International
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230522
PL  - England
TA  - EMBO J
JT  - The EMBO journal
JID - 8208664
RN  - 0 (Phospholipid Transfer Proteins)
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (Phosphatidylserines)
RN  - 0 (Xkr8 protein, mouse)
RN  - 0 (Membrane Proteins)
SB  - IM
MH  - Animals
MH  - Mice
MH  - *Phospholipid Transfer Proteins/genetics
MH  - *Apoptosis Regulatory Proteins/metabolism
MH  - Apoptosis
MH  - Phosphatidylserines/metabolism
MH  - Axons/metabolism
MH  - Neuronal Plasticity
MH  - Mammals
MH  - Membrane Proteins/metabolism
PMC - PMC10350823
OTO - NOTNLM
OT  - callosal projections
OT  - circuit maturation
OT  - phosphatidylserine
OT  - phospholipid scrambling
OT  - synaptic pruning
COIS- The authors declare that they have no conflict of interest.
EDAT- 2023/05/22 06:41
MHDA- 2023/07/18 13:09
PMCR- 2023/05/22
CRDT- 2023/05/22 03:53
PHST- 2023/04/18 00:00 [revised]
PHST- 2022/05/31 00:00 [received]
PHST- 2023/04/25 00:00 [accepted]
PHST- 2023/07/18 13:09 [medline]
PHST- 2023/05/22 06:41 [pubmed]
PHST- 2023/05/22 03:53 [entrez]
PHST- 2023/05/22 00:00 [pmc-release]
AID - EMBJ2022111790 [pii]
AID - 10.15252/embj.2022111790 [doi]
PST - ppublish
SO  - EMBO J. 2023 Jul 17;42(14):e111790. doi: 10.15252/embj.2022111790. Epub 2023 May 
      22.