RGD Reference Report - Characterization of a novel rat model of X-linked hydrocephalus by CRISPR-mediated mutation in L1cam. - Rat Genome Database

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Characterization of a novel rat model of X-linked hydrocephalus by CRISPR-mediated mutation in L1cam.

Authors: Emmert, A Scott  Vuong, Shawn M  Shula, Crystal  Lindquist, Diana  Yuan, Weihong  Hu, Yueh-Chiang  Mangano, Francesco T  Goto, June 
Citation: Emmert AS, etal., J Neurosurg. 2019 Feb 8:1-14. doi: 10.3171/2018.10.JNS181015.
RGD ID: 14695001
Pubmed: PMID:30738385   (View Abstract at PubMed)
DOI: DOI:10.3171/2018.10.JNS181015   (Journal Full-text)

OBJECTIVEEmergence of CRISPR/Cas9 genome editing provides a robust method for gene targeting in a variety of cell types, including fertilized rat embryos. The authors used this method to generate a transgenic rat L1cam knockout model of X-linked hydrocephalus (XLH) with human genetic etiology. The object of this study was to use diffusion tensor imaging (DTI) in studying perivascular white matter tract injury in the rat model and to characterize its pathological definition in histology.METHODSTwo guide RNAs designed to disrupt exon 4 of the L1cam gene on the X chromosome were injected into Sprague-Dawley rat embryos. Following embryo transfer into pseudopregnant females, rats were born and their DNA was sequenced for evidence of L1cam mutation. The mutant and control wild-type rats were monitored for growth and hydrocephalus phenotypes. Their macro- and microbrain structures were studied with T2-weighted MRI, DTI, immunohistochemistry, and transmission electron microscopy (TEM).RESULTSThe authors successfully obtained 2 independent L1cam knockout alleles and 1 missense mutant allele. Hemizygous male mutants from all 3 alleles developed hydrocephalus and delayed development. Significant reductions in fractional anisotropy and axial diffusivity were observed in the corpus callosum, external capsule, and internal capsule at 3 months of age. The mutant rats did not show reactive gliosis by then but exhibited hypomyelination and increased extracellular fluid in the corpus callosum.CONCLUSIONSThe CRISPR/Cas9-mediated genome editing system can be harnessed to efficiently disrupt the L1cam gene in rats for creation of a larger XLH animal model than previously available. This study provides evidence that the early pathology of the periventricular white matter tracts in hydrocephalus can be detected in DTI. Furthermore, TEM-based morphometric analysis of the corpus callosum elucidates the underlying cytopathological changes accompanying hydrocephalus-derived variations in DTI. The CRISPR/Cas9 system offers opportunities to explore novel surgical and imaging techniques on larger mammalian models.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
L1CAMHumanX-Linked Hydrocephalus  ISOL1cam (Rattus norvegicus) RGD 
L1camMouseX-Linked Hydrocephalus  ISOL1cam (Rattus norvegicus) RGD 
L1camRatX-Linked Hydrocephalus  IMP  RGD 
L1camem2JgnRatX-Linked Hydrocephalus  IMP  RGD 
SD-L1camem2JgnRatX-Linked Hydrocephalus MODEL: spontaneousIMP  RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
L1camRatabnormal corpus callosum morphology  IMP  RGD 
L1camRatenlarged fourth ventricle  IMP  RGD 
L1camRatenlarged lateral ventricles  IMP  RGD 
L1camRatpostnatal growth retardation  IMP  RGD 
Objects Annotated

Genes (Rattus norvegicus)
L1cam  (L1 cell adhesion molecule)
L1camem2Jgn  (L1 cell adhesion molecule;CRISPR/Cas9 induced mutant2,JGN)

Genes (Mus musculus)
L1cam  (L1 cell adhesion molecule)

Genes (Homo sapiens)
L1CAM  (L1 cell adhesion molecule)

SD-L1camem2Jgn  (NA)

Additional Information