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Hum Mol Genet. 2017 Jan 1;26(1):90-108. doi: 10.1093/hmg/ddw370.

Early born neurons are abnormally positioned in the doublecortin knockout hippocampus.

Author information

1
INSERM UMR-S 839, Paris.
2
Sorbonne Universités, Université Pierre et Marie Curie, Paris.
3
Institut du Fer à Moulin, Paris, France.
4
Plateforme de Transcriptomique, Laboratoire de Recherche Translationnelle, CEA/DSV/IG-Centre National de Genotypage, 2 rue Gaston Crémieux, Evry, France.
5
Ecole Normale Supérieure, Institut de Biologie de l'ENS, IBENS, Paris, France.
6
INSERM, U1024, Paris, France.
7
CNRS, UMR 8197, Paris, France.
8
Plateforme post-génomique de la Pitié-Salpêtrière, Faculty of Medicine, Paris.
9
Sorbonne Universités, UPMC Paris 06, UMS30 LUMIC, plateforme d'histomorphologie, St Antoine, Paris.
10
Plateforme Affymetrix, Institut Curie, Hospital St Louis, Paris.
11
Plateforme Bio-informatique Paris Descartes, Faculté de Necker, 156 rue de Vaugirard, Paris.

Abstract

Human doublecortin (DCX) mutations are associated with severe brain malformations leading to aberrant neuron positioning (heterotopia), intellectual disability and epilepsy. The Dcx protein plays a key role in neuronal migration, and hippocampal pyramidal neurons in Dcx knockout (KO) mice are disorganized. The single CA3 pyramidal cell layer observed in wild type (WT) is present as two abnormal layers in the KO, and CA3 KO pyramidal neurons are more excitable than WT. Dcx KO mice also exhibit spontaneous epileptic activity originating in the hippocampus. It is unknown, however, how hyperexcitability arises and why two CA3 layers are observed.Transcriptome analyses were performed to search for perturbed postnatal gene expression, comparing Dcx KO CA3 pyramidal cell layers with WT. Gene expression changes common to both KO layers indicated mitochondria and Golgi apparatus anomalies, as well as increased cell stress. Intriguingly, gene expression analyses also suggested that the KO layers differ significantly from each other, particularly in terms of maturity. Layer-specific molecular markers and BrdU birthdating to mark the final positions of neurons born at distinct timepoints revealed inverted layering of the CA3 region in Dcx KO animals. Notably, many early-born 'outer boundary' neurons are located in an inner position in the Dcx KO CA3, superficial to other pyramidal neurons. This abnormal positioning likely affects cell morphology and connectivity, influencing network function. Dissecting this Dcx KO phenotype sheds light on coordinated developmental mechanisms of neuronal subpopulations, as well as gene expression patterns contributing to a bi-layered malformation associated with epilepsy.

PMID:
28007902
DOI:
10.1093/hmg/ddw370
[Indexed for MEDLINE]

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