RGD Reference Report - Impaired neural differentiation and glymphatic CSF flow in the Ccdc39 rat model of neonatal hydrocephalus: genetic interaction with L1cam. - Rat Genome Database

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Impaired neural differentiation and glymphatic CSF flow in the Ccdc39 rat model of neonatal hydrocephalus: genetic interaction with L1cam.

Authors: Emmert, A Scott  Iwasawa, Eri  Shula, Crystal  Schultz, Preston  Lindquist, Diana  Dunn, R Scott  Fugate, Elizabeth M  Hu, Yueh-Chiang  Mangano, Francesco T  Goto, June 
Citation: Emmert AS, etal., Dis Model Mech. 2019 Nov 21;12(11). pii: 12/11/dmm040972. doi: 10.1242/dmm.040972.
RGD ID: 150521527
Pubmed: PMID:31771992   (View Abstract at PubMed)
PMCID: PMC6898999   (View Article at PubMed Central)
DOI: DOI:10.1242/dmm.040972   (Journal Full-text)

Neonatal hydrocephalus affects about one child per 1000 births and is a major congenital brain abnormality. We previously discovered a gene mutation within the coiled-coil domain-containing 39 (Ccdc39) gene, which causes the progressive hydrocephalus (prh) phenotype in mice due to lack of ependymal-cilia-mediated cerebrospinal fluid (CSF) flow. In this study, we used CRISPR/Cas9 to introduce the Ccdc39 gene mutation into rats, which are more suitable for imaging and surgical experiments. The Ccdc39prh/prh mutants exhibited mild ventriculomegaly at postnatal day (P)5 that progressed into severe hydrocephalus by P11 (P<0.001). After P11, macrophage and neutrophil invasion along with subarachnoid hemorrhage were observed in mutant brains showing reduced neurofilament density, hypomyelination and increased cell death signals compared with wild-type brains. Significantly more macrophages entered the brain parenchyma at P5 before hemorrhaging was noted and increased expression of a pro-inflammatory factor (monocyte chemoattractant protein-1) was found in the cortical neural and endothelial cells in the mutant brains at P11. Glymphatic-mediated CSF circulation was progressively impaired along the middle cerebral artery from P11 as mutants developed severe hydrocephalus (P<0.001). In addition, Ccdc39prh/prh mutants with L1 cell adhesion molecule (L1cam) gene mutation, which causes X-linked human congenital hydrocephalus, showed an accelerated early hydrocephalus phenotype (P<0.05-0.01). Our findings in Ccdc39prh/prh mutant rats demonstrate a possible causal role of neuroinflammation in neonatal hydrocephalus development, which involves impaired cortical development and glymphatic CSF flow. Improved understanding of inflammatory responses and the glymphatic system in neonatal hydrocephalus could lead to new therapeutic strategies for this condition.This article has an associated First Person interview with the joint first authors of the paper.



Disease Annotations    
hydrocephalus  (IMP,ISO)
Ventriculomegaly  (IMP,ISO)

Phenotype Annotations    
Objects Annotated

Genes (Rattus norvegicus)
Ccdc39  (coiled-coil domain containing 39)
Ccdc39em1Jgn  (coiled-coil domain containing 39; CRISPR/Cas9 induced mutant 1, Jgn)

Genes (Mus musculus)
Ccdc39  (coiled-coil domain containing 39)

Genes (Homo sapiens)
CCDC39  (coiled-coil domain containing 39)

Strains
SD-Ccdc39em1Jgn  (NA)


Additional Information