Expression of a new mutation (Axd) causing axial defects in mice correlates with maternal phenotype and age

Abstract

A new autosomal mutation, Axd (axial defects), is described. Axd segregates in a simple Mendelian fashion, and it is dominant with incomplete penetrance and variable expressivity. The phenotype of Axd heterozygotes ranges from a variety of tail anomalies to visibly normal tails. Approximately 12% of neonates from curly-tail (CT) F1 (Axd/+) x F1 (Axd/+) matings exhibit open neural tube defects (NTD) in the lumbosacral region and 16% have curly tails. Mean litter sizes and resorption rates comparable to wild type indicate that homozygosity for Axd is not obligately lethal. Genetic background plays a major role in Axd expression. Strains such as BALB/cByJ allow the highest penetrance of the mutation in single dose (46%), whereas, in CF-1 mice Axd is recessive. The tail phenotype of heterozygous Axd/+ dams, in part reflective of their genetic background, correlates with the incidence of NTD in F2 offspring: CT mothers produce significantly more neonates with frank NTD than normal tail mothers. At the one embryonic period examined for this study (D13/D14 post-coitus), an 85% higher incidence of total axial defects is observed than among the F2 at birth. Unchanging litter size and the relative increase in phenotypically normal offspring by birth suggest that Axd acts by delaying posterior neural tube closure. One of the most significant findings in this study is that maternal age influences the survival of Axd embryos in utero. Axd/+ dams older than 8 months yield fewer mean implants, higher resorption rates, and fewer viable embryos with axial defects than do Axd/+ dams younger than 8 months. Axd is not allelic to nor linked to the Sp (splotch) gene which also affects neurulation.

Over-expression of Grhl2 causes spina bifida in the Axial defects mutant mouse

“…In order to map the mutation underlying the Axd phenotype, a congenic strain was first generated on the BALB/c genetic background, selected for high penetrance of the dominant (heterozygous) phenotype (11). In the recombinant line, 97% of alleles tested were homozygous BALB/c.…”

“…The Axial defects ( Axd ) mutation arose spontaneously in the 1980s and was recognized on the basis of a curled tail phenotype inherited as a semi-dominant Mendelian trait (11). The penetrance of tail defects among Axd/+ mice varies with genetic background, being highest on the BALB/c background with ∼50–60% of mice affected (12).…”

“…The penetrance of tail defects among Axd/+ mice varies with genetic background, being highest on the BALB/c background with ∼50–60% of mice affected (12). Intercrosses of heterozygotes produced litters containing neonates with spina bifida, presumed to be homozygous mutants (11). At embryonic day (E) 12.5, ∼25% of embryos showed spina bifida, suggesting that spinal NTDs are fully penetrant among homozygotes at this stage (12).…”

“…Among neonates, there was a lower incidence of curled tails and spina bifida than expected. This was suggested to indicate possible correction of tail defects and/or soft tissue healing over open lesions during late gestation (11,12). However, inability to genotype litters precluded further analysis of this possibility.…”

Animal models of neural tube defects

“…We speculate that there might be an analogous relationship of Essien et al, 1990;2, Essien, 1992;3, Wallace et al, 1978;4, Anderson, 1981;5, Copp et al, 1994;6, Homanics et al, 1993;7, Homanics et al, 1995;8, Stumpo et al, 1995;9, Wu et al, 1996;10, Chen et al, 1996;11, Sah et al, 1995;12, Armstrong et al, 1995;13, Tyan, 1992;14, Embury et al, 1979;15, Copp et al, 1990;16, Copp et al, 1988;17, Matsuda, 1990;18, Vogelweid et al, 1993;19, Juriloff et al, 1989;20, Harris et al, 1994;21, Gunn et al, 1996;22, Padmanabhan and Ahmed, 1996. cranial closure with foregut growth or with PKC activity. Genetically, NTD susceptibility appears to be multifactorial and complex.…”