Selective inactivation of LGI1 in neuronal precursor cells leads to cortical dysplasia in mice

Research output: Contribution to journalArticle

Abstract

Constitutional mutations in Leucine-rich glioma inactivated 1 (LGI1) predispose to an autosomal dominant epilepsy syndrome in humans and germline inactivation of LGI1 in mice leads to early onset seizures. LGI1 is highly expressed in the regions involved in neuronal stem cell generation and migration and detailed analysis of the brains in these mice reveals a subtle cortical dysplasia characterized by hypercellularity in the outer cortical layers. To investigate the cellular origin for this cortical dysplasia, we created mice that allow cell-specific, conditional inactivation of LGI1. Exons 3–4, which contain critical motifs for LGI1 function, were targeted for deletion and, using a CMV-cre mouse strain, global inactivation of LGI1 led to early onset seizures and the same cortical dysplasia seen in the constitutionally null mice. Similarly, inactivation of LGI1 in cells expressing Nestin, expressed primarily in neuronal precursor cells, led to early onset seizures and cortical dysplasia. In contrast, targeting inactivation of LGI1 in cells expressing Gfap, Camk2a, and parvalbumin, did not lead to cortical dysplasia. This strain of mouse, therefore, allows for a more refined investigation of the cell types involved in the cortical dysplasia seen following inactivation of LGI1 and potentially a better understanding of the molecular mechanisms behind LGI1-induced epilepsy.

Original languageEnglish (US)
Article numbere23268
JournalGenesis
Volume57
Issue number2
DOIs
StatePublished - Feb 1 2019

Fingerprint

Malformations of Cortical Development
Leucine
Glioma
Seizures
Epilepsy
Parvalbumins
Nestin
Cell Movement
Exons
Stem Cells

Keywords

  • LGI1
  • conditional knockout
  • cortical dysplasia
  • epilepsy
  • neuronal stem cells

ASJC Scopus subject areas

  • Genetics
  • Endocrinology
  • Cell Biology

Cite this

Selective inactivation of LGI1 in neuronal precursor cells leads to cortical dysplasia in mice. / Silva, Maria J; Qin, Haiyan; Cowell, John Kenneth.

In: Genesis, Vol. 57, No. 2, e23268, 01.02.2019.

Research output: Contribution to journalArticle

@article{5b5b57faa1fb42cda02a544f4946bd83,
title = "Selective inactivation of LGI1 in neuronal precursor cells leads to cortical dysplasia in mice",
abstract = "Constitutional mutations in Leucine-rich glioma inactivated 1 (LGI1) predispose to an autosomal dominant epilepsy syndrome in humans and germline inactivation of LGI1 in mice leads to early onset seizures. LGI1 is highly expressed in the regions involved in neuronal stem cell generation and migration and detailed analysis of the brains in these mice reveals a subtle cortical dysplasia characterized by hypercellularity in the outer cortical layers. To investigate the cellular origin for this cortical dysplasia, we created mice that allow cell-specific, conditional inactivation of LGI1. Exons 3–4, which contain critical motifs for LGI1 function, were targeted for deletion and, using a CMV-cre mouse strain, global inactivation of LGI1 led to early onset seizures and the same cortical dysplasia seen in the constitutionally null mice. Similarly, inactivation of LGI1 in cells expressing Nestin, expressed primarily in neuronal precursor cells, led to early onset seizures and cortical dysplasia. In contrast, targeting inactivation of LGI1 in cells expressing Gfap, Camk2a, and parvalbumin, did not lead to cortical dysplasia. This strain of mouse, therefore, allows for a more refined investigation of the cell types involved in the cortical dysplasia seen following inactivation of LGI1 and potentially a better understanding of the molecular mechanisms behind LGI1-induced epilepsy.",
keywords = "LGI1, conditional knockout, cortical dysplasia, epilepsy, neuronal stem cells",
author = "Silva, {Maria J} and Haiyan Qin and Cowell, {John Kenneth}",
year = "2019",
month = "2",
day = "1",
doi = "10.1002/dvg.23268",
language = "English (US)",
volume = "57",
journal = "Genesis",
issn = "1526-954X",
publisher = "Wiley-Liss Inc.",
number = "2",

}

TY - JOUR

T1 - Selective inactivation of LGI1 in neuronal precursor cells leads to cortical dysplasia in mice

AU - Silva, Maria J

AU - Qin, Haiyan

AU - Cowell, John Kenneth

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Constitutional mutations in Leucine-rich glioma inactivated 1 (LGI1) predispose to an autosomal dominant epilepsy syndrome in humans and germline inactivation of LGI1 in mice leads to early onset seizures. LGI1 is highly expressed in the regions involved in neuronal stem cell generation and migration and detailed analysis of the brains in these mice reveals a subtle cortical dysplasia characterized by hypercellularity in the outer cortical layers. To investigate the cellular origin for this cortical dysplasia, we created mice that allow cell-specific, conditional inactivation of LGI1. Exons 3–4, which contain critical motifs for LGI1 function, were targeted for deletion and, using a CMV-cre mouse strain, global inactivation of LGI1 led to early onset seizures and the same cortical dysplasia seen in the constitutionally null mice. Similarly, inactivation of LGI1 in cells expressing Nestin, expressed primarily in neuronal precursor cells, led to early onset seizures and cortical dysplasia. In contrast, targeting inactivation of LGI1 in cells expressing Gfap, Camk2a, and parvalbumin, did not lead to cortical dysplasia. This strain of mouse, therefore, allows for a more refined investigation of the cell types involved in the cortical dysplasia seen following inactivation of LGI1 and potentially a better understanding of the molecular mechanisms behind LGI1-induced epilepsy.

AB - Constitutional mutations in Leucine-rich glioma inactivated 1 (LGI1) predispose to an autosomal dominant epilepsy syndrome in humans and germline inactivation of LGI1 in mice leads to early onset seizures. LGI1 is highly expressed in the regions involved in neuronal stem cell generation and migration and detailed analysis of the brains in these mice reveals a subtle cortical dysplasia characterized by hypercellularity in the outer cortical layers. To investigate the cellular origin for this cortical dysplasia, we created mice that allow cell-specific, conditional inactivation of LGI1. Exons 3–4, which contain critical motifs for LGI1 function, were targeted for deletion and, using a CMV-cre mouse strain, global inactivation of LGI1 led to early onset seizures and the same cortical dysplasia seen in the constitutionally null mice. Similarly, inactivation of LGI1 in cells expressing Nestin, expressed primarily in neuronal precursor cells, led to early onset seizures and cortical dysplasia. In contrast, targeting inactivation of LGI1 in cells expressing Gfap, Camk2a, and parvalbumin, did not lead to cortical dysplasia. This strain of mouse, therefore, allows for a more refined investigation of the cell types involved in the cortical dysplasia seen following inactivation of LGI1 and potentially a better understanding of the molecular mechanisms behind LGI1-induced epilepsy.

KW - LGI1

KW - conditional knockout

KW - cortical dysplasia

KW - epilepsy

KW - neuronal stem cells

UR - http://www.scopus.com/inward/record.url?scp=85058988788&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85058988788&partnerID=8YFLogxK

U2 - 10.1002/dvg.23268

DO - 10.1002/dvg.23268

M3 - Article

VL - 57

JO - Genesis

JF - Genesis

SN - 1526-954X

IS - 2

M1 - e23268

ER -