Retinoic acid‐induced selective mortality of splotch‐delayed mouse neural tube defect mutants

Abstract

The allelic loci splotch (Sp) and splotch-delayed (Spd) cause neural tube defects (NTDs) in mice homozygous for either of these genes. The polymorphic enzyme isocitrate dehydrogenase (Idh-1) in conjunction with a recombination suppressor was used as a genetic marker to identify embryos homozygous for these alleles. A split dose of all-trans retinoic acid (RA) totalling 5.0 mg/kg administered on gestation day 9/15 and 9/18 (days/h) significantly reduced the frequencies of NTD and of mutant genotypes in marked Spd embryos examined on day 16 without significantly increasing the resorption frequency. There was a nonsignificant decrease in the frequencies of NTD and mutant genotypes in embryos examined on day 11 of gestation. Thus, retinoic acid treatment was associated with selective mortality of the homozygous Spd mutants. No evidence of selective mortality was observed in RA-treated Sp embryos.

The Cause of Chiari II Malformation: A Unified Theory

“…To date, available evidence in dicates that neurulation is a combination of intercellu lar and extracellular interactions that are under the direction of the genome [42]. One example of a genetic cause is the autosomal recessive Splotch mutation; cau dal neural tube defects occur in mice homozygous (Spd/Spd) for this gene [18,33,44], Our laboratory has observed notable differences in the time and type of expression of several glycoproteins in Splotch embryos with neural tube defects compared with normal littermates [19]. Complex carbohydrates, i.e., glycoconjugates, on the cell surface and within the extracellular matrix provide some of the required sig nals for cellular differentiation and maturation [3,12,38,42,45,56].…”

Modifier locus for exencephaly inCecr2mutant mice is syntenic to the 10q25.3 region associated with neural tube defects in humans

“…These models may be useful in studying human NTDs, which also show a multifactorial inheritance pattern. In addition, many mouse mutants, including the Sp (29), ct (31), Ski (11), and Cecr2 (4) mutant lines, are highly susceptible to genetic background effects, and strain-dependent incomplete penetrance is very common, but little is known about such modifier loci. The etiology of human NTDs makes the identification of low penetrance or minor effect genes in mice even more compelling, as human NTDs likely result from a summation of gene variants with minor effects and environmental factors.…”

Diabetic Embryopathy in C57BL/6J Mice

“…The penetrance of NTDs is highly variable, depending on genetic background (19,20). C57BL/6J Sp/Sp mice reportedly exhibit 100% spina bifida aperta and 56% exencephaly (16), while outcrossing to In(1)1Rk mice, in one laboratory, resulted in only 25% spina bifida aperta but 100% exencephaly in Sp/Sp progeny (19,21). Sp has been associated with gene-teratogen interactions, resulting in increased sensitivity to NTDs caused by retinoic acid (22)(23)(24) and arsenite (25).…”