Dr. Diana Juriloff, Research Supervisor (Medical Genetics)
Dr. Louis Lefebrve (Medical Genetics)
Dr. Muriel Harris, Research Supervisor (Medical Genetics)
Dr. Dixie Mager (Medical Genetics)
EXAMINING COMMITTEE
Chair: Dr. Jan Friedman (Medical Genetics)
Supervisory Committee: Dr. Diana Juriloff, Research
Supervisor (Medical Genetics), Dr. Muriel Harris, Research Supervisor (Medical
Genetics), Dr. Dixie Mager (Medical Genetics)
University Examiners: Dr. Laura Arbour (Medical Genetics)
External Examiner: To be completed by FoGS
ABSTRACT
The SELH/Bc mouse strain, a model for multifactorial human
neural tube
defects, has 10-30% exencephaly depending on the maternal
diet. Developmental studies have found that midbrain fold elevation is delayed
in all SELH/Bc embryos and that they omit Closure 2, a normal site of initiation
of contact of neural folds during cranial neural tube closure. Previous studies have
found the genetic exencephaly risk to be due to a combination of three
genes, Exen1, Exen2, and Exen3, acting additively. Exen1 and Exen2 had been mapped
to regions on Chr 13 and Chr 5, respectively, and Exen3 provisionally to Chr
11. My studies further investigated the genetic cause of this defect using F2
exencephaly panels and congenic lines, as well as the diet effect that is
observed in SELH/Bc. The frequencies of exencephaly were observed in F2
segregants from crosses between SELH/Bc and a normal unrelated strain, LM/Bc.
There were two F2 exencephaly panels collected, one from mice fed the regular
diet Purina Laboratory Rodent Diet #5001 and one from mice fed the high-risk
diet Purina Mouse Diet #5015 (“PMD #5015”) that increases exencephaly frequency
in SELH/Bc. There was a significant increase in exencephaly frequency in the F2
embryos when mice were fed PMD #5015. A new locus on Chr 7 that contributed to
the risk of exencephaly in the F2 embryos, named Exen4, was established as
well. The congenic lines that had been created by transferring the normal Exen1
and Exen2 alleles from LM/Bc into the SELH/Bc background and the Exen1 and Exen2
alleles from SELH/Bc into the LM/Bc background confirmed the locations of the
Exen1 and Exen2 loci, and demonstrated that exencephaly in SELH/Bc is a multifactorial
threshold trait. The congenic lines with Exen1 alleles from SELH/Bc responded
to PMD #5015 supporting the hypothesis of a gene-diet interaction. Morphological
studies of the cranial neural tube closure patterns in congenic line embryos
supported the hypothesis that the liability trait for exencephaly (multifactorial
threshold defect) is timing of mesencephalon fold elevation as the congenic
line embryos showed detectable delay or acceleration of elevation of mesencephalon
folds compared to their respective parental strain.
PRESENTATIONS
Poster, Teratology Society Annual Meeting, 2004
Poster, Medical Genetics Research Day, 2004
AWARDS
Summer Biology Fellowship, Colorado State University, 2001
GRADUATE STUDIES
Field of Study: Genetics and embryology of multifactorial
neural tube defects in mouse models, Department of Medical Genetics
Courses
MEDG 505 Genome Analysis Dr. Hieter / Dr. Jones
MEDG 515 Mammalian Developmental Genetics Dr.
Juriloff / Dr. Harris
MEDG 520 Advanced Human Molecular Genetics Dr. McMaster
MEDG 530 Advanced Human Genetics Dr. Friedman
MEDG 545 Current Topics – Medical Genetics Dr. Juriloff, Dr. Harris
MEDG 548 Directed Studies Dr. Juriloff, Dr. Harris
