Mary J. Seller

Six1 and Six4 homeoproteins are required for Pax3 and Mrf expression during myogenesis in the mouse embryo

In mammals, Six5, Six4 and Six1 genes are co-expressed during mouse myogenesis. Six4 and Six5 single knockout (KO) mice have no developmental defects, while Six1 KO mice die at birth and show multiple organ developmental defects. We have generated Six1Six4 double KO mice and show an aggravation of the phenotype previously reported for the single Six1 KO. Six1Six4 double KO mice are characterized by severe craniofacial and rib defects, and general muscle hypoplasia. At the limb bud level, Six1 and Six4 homeogenes control early steps of myogenic cell delamination and migration from the somite through the control of Pax3 gene expression. Impaired in their migratory pathway, cells of the somitic ventrolateral dermomyotome are rerouted, lose their identity and die by apoptosis. At the interlimb level, epaxial Met expression is abolished, while it is preserved in Pax3-deficient embryos. Within the myotome, absence of Six1 and Six4 impairs the expression of the myogenic regulatory factors myogenin and Myod1, and Mrf4 expression becomes undetectable. Myf5 expression is correctly initiated but becomes restricted to the caudal region of each somite. Early syndetomal expression of scleraxis is reduced in the Six1Six4 embryo, while the myotomal expression of Fgfr4 and Fgf8 but not Fgf4 and Fgf6 is maintained. These results highlight the different roles played by Six proteins during skeletal myogenesis.

Neural Tube Defects in Curly-Tail Mice. II. Effect of Maternal Administration of Vitamin A

Vitamin A, a known teratogen of the central nervous system, was administered in various doses, at the time of active neural tube closure, to pregnant curly-tail mice which have a genetic predisposition to neural tube defects (n. t. d. ), and to A Strong mice, which are not so predisposed. The curly-tail mice showed an enhanced susceptibility to the teratogenic effect of vitamin A given on day 8 of gestation, demonstrating a clear gene─environment interaction. There was a differential response by the two sexes. Females seemed to be more affected by the vitamin A than males. When vitamin A was administered on day 9, instead of day 8, of gestation, the incidence of n. t. d. decreased rather than increased. Furthermore, the number of mice affected by n. t. d. was markedly lower even than that found spontaneously in untreated curly-tail mice.

Neural tube defects in curly-tail mice. I. Incidence, expression and similarity to the human condition

The incidence of neurovertebral defects in mutant mice of the curly-tail strain was investigated and found to be similar to that observed in the same mice twenty-five years ago. The results of breeding experiments support the hypothesis of Grüneberg that the defects in these mice are probably caused by a recessive gene, the expression of which is markedly affected by the genetic background. Selection against the curly-tail phenotype for six generations did not affect the incidence of abnormalities. A marked excess of females was found among exencephalic mice, as among humans with neural tube defects. Similarly, polyhydramnios, hydrocephaly, high levels of amniotic fluid alphafoetoprotein and distinctive, rapidly adhering cells in the amniotic fluid also occurred in these mice, as in humans. The curly-tail mice thus provide a useful model for the investigation of neural tube defects in man.

Dominant optic atrophy : Refining the clinical diagnostic criteria in light of genetic linkage studies

OBJECTIVE To describe the clinical findings and refine the clinical diagnostic criteria for dominant optic atrophy based on eight British families in which the diagnosis was confirmed by linkage analysis. DESIGN AND PARTICIPANTS Case series; 92 subjects in 8 pedigrees had both eyes examined. INTERVENTION Family members received a domiciliary examination based on best-corrected visual acuity, color vision using Ishihara and Hardy Richter Rand (HRR) plates, confrontation field testing using a red target, and optic disc evaluation using a direct ophthalmoscope. Genomic DNA was extracted from leukocytes or buccal mucosal cells and genotyped using 12 fluorescently labeled microsatellite markers from the region 3q27-q29. MAIN OUTCOME MEASURES Subjects were classified clinically as definitely or possibly affected on the basis of the domiciliary examination before genetic analysis, and these results were compared with the haplotype analysis. RESULTS Clinically, 43 subjects were identified as definitely affected, 4 as possibly affected, and 45 as unaffected. Visual acuity in affected subjects ranged from 6/6 to count fingers and declined with age. On genetic analysis, a haplotype was identified in each family, which was found in all definitely affected members but not in those regarded as unaffected. The four possibly affected individuals also bore the haplotype that segregated with the disease. CONCLUSIONS Simple clinical tests are highly efficacious in diagnosing dominant optic atrophy. Contrary to accepted criteria, symptoms begin before the age of 10 years in only 58% of affected individuals. Visual acuity in affected subjects is highly variable. A mild degree of temporal or diffuse pallor of the optic disc and minimal color vision defects, in the context of a family with dominant optic atrophy, are highly suggestive of an individual being affected, even if the visual acuity is normal. This widens the generally accepted diagnostic criteria for this disease.

Phenotypic variation in Meckel syndrome

Four sibs are described with Meckel syndrome, an autosomal recessive disorder with multiple abnormalities. Each sib manifested only two of the three cardinal signs of Meckel syndrome ‐ encephalocoele and polycystic kidneys, lacking Polydactyly. The literature is examined to assess the phenotypic variation of the condition: 57 % of cases have all the three major abnormalities, 16% have the two found in this family, and the remainder exhibit other variations. In 9 of 17 families where more than one sib is affected, manifestation between sibs is the same, but in the only other two families with as many as four affected sibs, there is variation in expression between sibs.

The curly-tail mouse: An experimental model for human neural tube defects

Abstract Many aspects of the open lesions of the neural tube observed in the curly-tail mice are similar to those seen in man. In the mouse, the cause of the defects is a recessive gene, the expression of which is modified by the rest of the genome. A marked interaction between genetic and environmental factors was also observed in this strain of mice, thus suggesting that it represents a useful model to investigate the origin of the neural tube defects (NTD) in man. In the mutant strain, the interaction between the curly-tail gene and the environmental factors has been investigatigated using known teratogenic compounds, as well as hormones and vitamins, which it was hoped would prevent the malformations. An intriguing result was to observe that, while, as expected, excess of vitamin A increases the incidence of NTD, low doses, given at a particular stage of gestation, prevent the manifestation of the abnormalities. To investigate further the interaction between genetic and environmental factors and to provide some insight into the mechanisms underlying NTD in man, the effects of Trypan blue, hydroxyurea, progesterone, cortisone and vitamin E were also investigated in curly-tail mice and the results reported in this review.

Investigation of folate intake and metabolism in women who have had two pregnancies complicated by neural tube defects

Object To investigate folate intake and blood levels of folic acid and vitamin C in women with and without a history of two NTD‐affected pregnancies and to measure the increase in serum folate following ingestion of orange juice.

Two sibs with anophthalmia and pulmonary hypoplasia (the Matthew-Wood syndrome).

We describe two sibs with pulmonary hypoplasia and anophthalmia; one also had a number of other malformations. Only one other broadly similar case could be found in the literature, and it was an isolated occurrence. The condition is named the Matthew-Wood syndrome.

POLYACRYLAMIDE GEL ELECTROPHORESIS OF AMNIOTIC FLUID CHOLINESTERASES: A GOOD PRENATAL TEST FOR NEURAL TUBE DEFECTS

The qualitative assay of the cholinesterases (ChE) in amniotic fluid on polyacrylamide gel gave a single major band (cholinesterase) in all samples from normal pregnancies, and two major bands (cholinesterase and acetylcholinesterase) in all cases from fetuses with open neural tube defects. Five fluids which were true false positive on alpha‐fetoprotein (AFP) assay (elevated AFP in a clear fluid but normal fetus) had a single band, and two fluids which were false negative on AFP testing (normal AFP but spina bifida fetus) had two bands. The second ‘diagnostic’ ChE band sometimes occurred, together with other extra bands, in some fluids which were very severely contaminated by maternal or fetal blood, but in four of six fluids from normal fetuses where fetal blood staining was sufficient to cause the AFP to be elevated, there was only one ChE band. It is suggested that the qualitative assay of ChE should be performed in addition to AFP in the prenatal diagnosis of neural tube defects.

ELEVATED LEVELS OF MATERNAL PLASMA ALPHA‐FETOPROTEIN AFTER AMNIOCENTESIS

An elevation of maternal AFP levels was observed in 11 of 65 cases (17 per cent) after amniocentesis. It is suggested that blood samples in which AFP levels are to be measured should always be collected before and not after amniocentesis.