SrGAP3 knockout mice display enlarged lateral ventricles and specific cilia disturbances of ependymal cells in the third ventricle

Abstract

In several mouse models of mental retardation, ventricular enlargements have been observed. Mutation in the SrGAP3 gene residing on chromosome 3p25 has previously been associated with intellectual disability in humans. In addition, SrGAP3 is related to Rho-GAPs signaling pathways, which play essential roles in the development and plasticity of the nervous system. About 10 % of postnatal homozygous SrGAP3-deficient mice die due to hydrocephalus, whereas the remaining mice survive into adulthood but display enlarged ventricles. We analyze the ventricular enlargement of these mice by performing a post-mortem MRI approach. We found a more than 15-fold enlargement of the lateral ventricles of homozygous SrGAP3-deficient mice. Moreover, we demonstrate that this phenotype was not accompanied by a stenosis of the aqueduct. Instead, SrGAP3 knockout mice displayed reduced densities of cilia of ependymal cells in These third ventricle compared to age-matched controls. This results indicate that the ventricular enlargement may be due to ciliopathy.

Neural cell adhesion molecule Negr1 deficiency in mouse results in structural brain endophenotypes and behavioral deviations related to psychiatric disorders

“…Enlarged ventricles observed in Negr1 −/− mice have been correlated with the negative symptoms of schizophrenia 54 , psychotic behavior in depression 55 , and autistic behavior 56 . Enlargement of ventricles has also been observed in SCZ animal models like hDISC, Zic2 kd/ + , Df16A +/−, 22q11.2, CRMP2, NCAM180 48,57–60 , in an ASD model like 15q13.3 61 , and in SrGAP3 animal model of mental retardation 62 . These findings support the hypothesis of the genetic involvement of Negr1 in the pathogenesis of psychiatric disorders.…”

Beyond Axon Guidance: Roles of Slit-Robo Signaling in Neocortical Formation

“…In addition, rare copy number variations of SRGAP2C, a human-specific paralog of srGAP2, was identified in patients with ASD and intellectual disability (Dennis et al, 2012, Figure 3B). srGAP3-deficient mice demonstrate several behavioral abnormalities, including intellectual disabilityassociated behaviors and autism-associated behaviors (Kim et al, 2012;Waltereit et al, 2012;Koschützke et al, 2015;Bertram et al, 2016). srGAPs have been shown to play important roles in spine formation, and srGAP mutations are thought to cause intellectual disabilities, likely via abnormal spine formation.…”

CiliaCarta: An integrated and validated compendium of ciliary genes

“…elegans mutant allele data is consistent with ciliary functions for the associated genes, a few of these genes could orchestrate the observed phenotypes via non-ciliary roles or could be off-target effects (as is documented for morpholinos in zebrafish [30]). However, for two out of the three genes tested with zebrafish morpholinos (sr3gap and ttc18) a ciliary function has been established by others [31,32]. The high prevalence of cilia-related phenotypes in assayed mutants (e.g., roaming disruption [27,33–35]), implies a low (albeit not negligible) false negative rate and provides quantitative support for substantial enrichment of ciliary genes in CiliaCarta.…”