PMID- 35585091
OWN - NLM
STAT- MEDLINE
DCOM- 20220520
LR  - 20220716
IS  - 2041-1723 (Electronic)
IS  - 2041-1723 (Linking)
VI  - 13
IP  - 1
DP  - 2022 May 18
TI  - Novel role of the synaptic scaffold protein Dlgap4 in ventricular surface 
      integrity and neuronal migration during cortical development.
PG  - 2746
LID - 10.1038/s41467-022-30443-z [doi]
LID - 2746
AB  - Subcortical heterotopias are malformations associated with epilepsy and 
      intellectual disability, characterized by the presence of ectopic neurons in the 
      white matter. Mouse and human heterotopia mutations were identified in the 
      microtubule-binding protein Echinoderm microtubule-associated protein-like 1, 
      EML1. Further exploring pathological mechanisms, we identified a patient with an 
      EML1-like phenotype and a novel genetic variation in DLGAP4. The protein belongs 
      to a membrane-associated guanylate kinase family known to function in glutamate 
      synapses. We showed that DLGAP4 is strongly expressed in the mouse ventricular 
      zone (VZ) from early corticogenesis, and interacts with key VZ proteins including 
      EML1. In utero electroporation of Dlgap4 knockdown (KD) and overexpression 
      constructs revealed a ventricular surface phenotype including changes in 
      progenitor cell dynamics, morphology, proliferation and neuronal migration 
      defects. The Dlgap4 KD phenotype was rescued by wild-type but not mutant DLGAP4. 
      Dlgap4 is required for the organization of radial glial cell adherens junction 
      components and actin cytoskeleton dynamics at the apical domain, as well as 
      during neuronal migration. Finally, Dlgap4 heterozygous knockout (KO) mice also 
      show developmental defects in the dorsal telencephalon. We hence identify a 
      synapse-related scaffold protein with pleiotropic functions, influencing the 
      integrity of the developing cerebral cortex.
CI  - (c) 2022. The Author(s).
FAU - Romero, Delfina M
AU  - Romero DM
AUID- ORCID: 0000-0002-6602-1889
AD  - INSERM UMR-S 1270, F-75005, Paris, France.
AD  - Sorbonne University, F-75005, Paris, France.
AD  - Institut du Fer a Moulin, F-75005, Paris, France.
AD  - Instituto de Biologia Celular y Neurociencias "Prof. E. De Robertis" (IBCN), 
      Facultad de Medicina, Universidad de Buenos Aires, CONICET, Buenos Aires, 
      Argentina.
FAU - Poirier, Karine
AU  - Poirier K
AD  - INSERM UMR-S 1163, Translational Genetics, Imagine Institute, Paris Cite 
      University, Necker Enfants Malades University Hospital, Paris, France.
FAU - Belvindrah, Richard
AU  - Belvindrah R
AUID- ORCID: 0000-0002-8121-9826
AD  - INSERM UMR-S 1270, F-75005, Paris, France.
AD  - Sorbonne University, F-75005, Paris, France.
AD  - Institut du Fer a Moulin, F-75005, Paris, France.
FAU - Moutkine, Imane
AU  - Moutkine I
AD  - INSERM UMR-S 1270, F-75005, Paris, France.
AD  - Sorbonne University, F-75005, Paris, France.
AD  - Institut du Fer a Moulin, F-75005, Paris, France.
FAU - Houllier, Anne
AU  - Houllier A
AD  - INSERM UMR-S 1270, F-75005, Paris, France.
AD  - Sorbonne University, F-75005, Paris, France.
AD  - Institut du Fer a Moulin, F-75005, Paris, France.
FAU - LeMoing, Anne-Gaelle
AU  - LeMoing AG
AD  - Service of Pediatric Neurology, CHU Amiens, Amiens, France.
FAU - Petit, Florence
AU  - Petit F
AUID- ORCID: 0000-0002-1368-1023
AD  - Department of Clinical Genetics. Hopital Jeanne de Flandre, CHU Lille, F-59000, 
      Lille, France.
FAU - Boland, Anne
AU  - Boland A
AUID- ORCID: 0000-0001-8789-5676
AD  - National Center of Human Genomics Research (CNRGH), Francois Jacob Institute of 
      Biology, CEA, University Paris-Saclay, F-91057, Evry, France.
FAU - Collins, Stephan C
AU  - Collins SC
AD  - INSERM UMR-S 1231, University of Bourgogne Franche-Comte, 21000, Dijon, France.
FAU - Soiza-Reilly, Mariano
AU  - Soiza-Reilly M
AUID- ORCID: 0000-0002-5800-865X
AD  - Instituto de Fisiologia, Biologia Molecular y Neurociencias (IFIBYNE), CONICET, 
      Universidad de Buenos Aires, Buenos Aires, Argentina.
FAU - Yalcin, Binnaz
AU  - Yalcin B
AUID- ORCID: 0000-0002-1924-6807
AD  - INSERM UMR-S 1231, University of Bourgogne Franche-Comte, 21000, Dijon, France.
FAU - Chelly, Jamel
AU  - Chelly J
AUID- ORCID: 0000-0002-0939-8719
AD  - IGBMC-CNRS UMR-S 7104, INSERM UMR-S 964, Strasbourg, France.
FAU - Deleuze, Jean-Francois
AU  - Deleuze JF
AUID- ORCID: 0000-0002-5358-4463
AD  - National Center of Human Genomics Research (CNRGH), Francois Jacob Institute of 
      Biology, CEA, University Paris-Saclay, F-91057, Evry, France.
FAU - Bahi-Buisson, Nadia
AU  - Bahi-Buisson N
AD  - Laboratory of Genetics and Development of the Cerebral Cortex, INSERM UMR-S 1163, 
      Imagine Institute, Paris, France.
AD  - Paris Cite University, Imagine Institute, Paris, France.
AD  - Pediatric Neurology APHP- Necker Enfants Malades University Hospital, Paris, 
      France.
AD  - Centre of Reference, Rare Causes of Intellectual Deficiences, APHP- Necker 
      Enfants Malades University Hospital, Paris, France.
FAU - Francis, Fiona
AU  - Francis F
AUID- ORCID: 0000-0001-8542-7537
AD  - INSERM UMR-S 1270, F-75005, Paris, France. fiona.francis@inserm.fr.
AD  - Sorbonne University, F-75005, Paris, France. fiona.francis@inserm.fr.
AD  - Institut du Fer a Moulin, F-75005, Paris, France. fiona.francis@inserm.fr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220518
PL  - England
TA  - Nat Commun
JT  - Nature communications
JID - 101528555
RN  - 0 (Dlgap4 protein, mouse)
RN  - 0 (SAP90-PSD95 Associated Proteins)
SB  - IM
MH  - Animals
MH  - Cell Movement/genetics
MH  - Cerebral Cortex/metabolism
MH  - *Classical Lissencephalies and Subcortical Band Heterotopias/metabolism/pathology
MH  - Humans
MH  - Mice
MH  - Mice, Knockout
MH  - Neurogenesis/genetics
MH  - Neurons/physiology
MH  - SAP90-PSD95 Associated Proteins/*metabolism
PMC - PMC9117333
COIS- The authors declare no competing interests.
EDAT- 2022/05/19 06:00
MHDA- 2022/05/21 06:00
PMCR- 2022/05/18
CRDT- 2022/05/18 23:18
PHST- 2019/07/23 00:00 [received]
PHST- 2022/04/29 00:00 [accepted]
PHST- 2022/05/18 23:18 [entrez]
PHST- 2022/05/19 06:00 [pubmed]
PHST- 2022/05/21 06:00 [medline]
PHST- 2022/05/18 00:00 [pmc-release]
AID - 10.1038/s41467-022-30443-z [pii]
AID - 30443 [pii]
AID - 10.1038/s41467-022-30443-z [doi]
PST - epublish
SO  - Nat Commun. 2022 May 18;13(1):2746. doi: 10.1038/s41467-022-30443-z.