Room: G 508, Biological Sciences
Phone: (780) 492-5377
Fax: (780) 492-9234
Mouse models of neural tube defects and reduced fertility
Neural tube defects (NTDs), including anencephaly and spina bifida, are the second most common birth defect in humans, with a frequency of approximately 1/1000 births. NTDs are caused by the failure of the neural tube to close during early development of the brain and spinal cord. Closure failure in the part of the neural tube that forms the brain results in anencephaly (called exencephaly in mice). The brain forms completely abnormally and the cranium is absent, resulting in death at birth.
We are studying the gene Cecr2, which when mutated causes exencephaly in mice (Banting et al, 2005). We study two different mutations of Cecr2, a deletion mutation causing exencephaly in 100% of mutants, and a gene trap mutation causing exencephaly in ~54% of mutants. In the latter strain, the surviving mutants show reduced fertility in both males and females (Thompson et al, 2012). The defect also depends on the mouse strain: the gene trap mutation on a BALB/c mouse strain shows exencepahly in ~54% of embryos, but this same mutation on the FVB/N mouse strain shows relatively normal brain development in all embryos (Banting et al, 2005, Dawe et al, 2011). We have mapped to mouse chromosome 19 genes that modify Cecr2-induced exencephaly, partially leading to the strain difference in susceptibility (Davidson et al, 2007, Kooistra et al, 2012). Exploration of Cecr2 and it’s major modifiers will add to our understanding of both neural tube defects and the mechanisms of normal neurulation.
Figure 1: Mouse embryo at 9 days gestation, just prior to closure of the cranial region of the neural tube. (picture – Erica Kubanek)
Figure 2: The gene trap mutation produces a CECR2-b-gal fusion protein and thereby allows us to track Cecr2 expression with X-gal staining. The 13.5 day embryo on the left is normal, being heterozygous for the gene-trap mutation, and shows staining in the developing brain as well as other tissues. The 13.5 day embryo on the right shows the neural tube defect exencephaly. (Banting et al, 2005)
Project #1 (Farshad Niri)
The structure and function of the Cecr2 remodelling complex
The protein CECR2 is involved in chromatin remodeling, and with SNF2L (SMARCA1) forms the CERF complex, with ATP-dependent chromatin remodeling activity (Banting et al, 2005). We are exploring this interaction and the downstream genes that CERF may act upon.
Project #2 (Renee Leduc)
Identifying major genetic modifiers of Cecr2-related exencephaly
We have mapped a major modifier locus to mouse chromosome 19 (Davidson et al, 2007, Figure 5). This site corresponds to 10q25.3, which is one of the few sites linked to NTD susceptibility in humans (Rampersaud et al, 2005, J. Med. Genet. 42;940-946). Therefore, identification of the modifier in Cecr2-mutant mice may shed light on NTD susceptibility in humans. We are currently examining candidate genes for this modifier. We have shown that the strain difference does not involve the location of closure site 2 (Figure 6), which has been associated in other studies with variation in NTD susceptibility (Fleming and Copp, 2000, Hum Mol Genet 9:575-581)
Figure 5: Genetic mapping to mouse chromosome 19 of a major modifier gene associated with exencephaly. (Davidson et al, 2007).
Figure 6: At 9 somites, both BALB/c (A) and FVB/N (B) wildtype strains show normal elevation of the neural folds and the location of closure site 2 at the same site, the forebrain midbrain boundary. Rostral scanning electron micrographs. FB (forebrain) MB (midbrain) (Davidson et al, 2007)
Project #3 (Kacie Norton)
The role of Cecr2 in reproduction
Figure : CECR2 stains strongly in the adult testes. X-gal staining of testes from mice heterozygous for the Cecr2 genetrap allele (left) and wildtype (right). (Picture by Erica Kubanek)
Last Modified:2013-08-04 |