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Biomedical subjects

D M Juriloff

Publications and source records attributed to D M Juriloff.

At least 55 records · Page 3Linked to original sources
PubMed1985

Thyroxine-induced differential mortality of cleft lip mouse embryos: dose- and time-response studies of the A/WySn strain.

Pregnant A/WySn mice, 20 to 30% of whose offspring have spontaneous cleft lip, were treated with thyroxine. Following treatment, cleft lip and normal embryos died, but cleft lip embryos died at a higher rate. The increased liability of cleft lip embryos to thyroxine-induced death was considered as a possible experimental route to identify the basic genetic defect that causes cleft lip. A time-response study indicated that cleft lip embryos responded more than normals following treatment on any of days 7 to 12 of gestation, that there is no sharply defined critical period, and that normal and cleft lip embryos do not differ in time of maximum sensitivity. A dose-response study showed linear responses of normal and cleft lip embryos on a probit-log dose scale, with a common slope and LD50's of 1.9 and 1.3 mg respectively. These dose-response properties indicate that normal and cleft lip embryos are probably killed by the same mechanism, but differ in dosage tolerance. That is, they differ quantitatively, not qualitatively. Thyroxine did not significantly change the cleft lip frequency, and the difference between normal and cleft lip embryos that leads to cleft lip itself is therefore not in the same pathway as that which leads to thyroxine-induced death. A hypothetical example of the defect basic to both pathways is presented.

Animals↗
PubMed1985

Prevention of the eye closure defect in lgMl/lgMl fetal mice by thyroxine.

The open-eye birth defect of mice caused by the lgMl mutation was prevented by prenatal administration of thyroxine (T4) to the pregnant mother. Treatment on days 10 to 11 of gestation was most effective in preventing open-eyes. A contrasting worsening of the defect was seen after treatment on day 14 of gestation. A dose-response relationship for prevention appeared to be present up to a dose of 0.1 mg/mouse, after which 39% of fetuses had both eyes closed compared to 2% in controls. Higher doses appeared to give little or no further increase in beneficial effect. Scanning electron microscopy was used to compare thyroxine-treated and untreated lgMl/lgMl and normal CBA/J day 16 or 17 fetal eyes. Mutant eye closure after thyroxine differed from untreated mutant in the growth of both upper and lower eyelids across the eye and in increased numbers of rounded periderm cells on the advancing lid edges. The underlying epithelial tissue layer appeared to fuse closed. The induced eye closure in the mutant was not normal, however. The periderm cell layer had disorderly fusion at the outer canthus, premature flattening, and failure to fuse in the inner canthus.

Animals↗
PubMed1985

Genetic and developmental studies of a new mouse mutation that produces otocephaly.

A new recessive lethal mutation in mice that produces the otocephaly defect is described. The mutation, provisionally named oto is located on chromosome 1, within, or just outside of, a previously existing inversion, In(1)1Rk, and was probably induced by X-irradiation. The penetrance of oto is nearly complete on C57BL strain backgrounds but is reduced to a variable extent on other backgrounds. The previously reported liability to spontaneous otocephaly in the C57BL strains appears to increase the penetrance of oto. Studies of the sequences of developmental changes (conducted primarily by scanning electron microscopy) and of the range of defects indicate that a primary deficiency involving the anterior aspect of the embryonic disc occurs in affected individuals. An hypothesis related to deficiencies in mesodermal populations is presented as the basis for the craniofacial and brain defects observed.

Animals↗
PubMed1984

Cortisone cure of the lidgap defect in fetal mice: a dose-response and time-response study.

Cortisone administered during pregnancy prevents the phenotypic expression of lidgap-Miller (lgM1), a genetically determined congenital defect in mice. The dose-response, on a probit log dose scale, is linear to a dose of 60 mg/kg maternal body weight, giving an observed maximum cure of 94% and an ED50(1) of 27 mg/kg. At higher doses the rate of prevention diminishes, to 56% at 320 mg/kg. Fetal (18-day) weight remains unaffected for doses of up to 60 mg/kg and then drops sharply at higher doses, suggesting that cortisone is toxic in this higher range. The severity of lidgap, measured in two ways (as one or both eyes open and as width of gap), decreases as its frequency falls. This finding is in keeping with the threshold model for birth defects. The threshold appears to be in the embryos rather than in their mothers. There is a broad optimum time of treatment: days 13-14 for the 80 mg/kg dose, and days 14-15 for the 30 mg/kg dose. Treatment on day 16 has little or no effect. It is not known how cortisone cures the lidgap trait. The action may be specific--to stimulate transcription of a specific gene, possibly of the lidgap locus itself--or more general, e.g., to alter cell division rate or extracellular matrix constituents.

Animals↗
PubMed1983

Abnormal head posture associated with induction of cleft palate by methylmercury in C57BL/6J mice.

Maternal treatment with methylmercury (MeHg) has been shown to induce a high frequency of cleft palate and produce growth retardation in rat and mouse fetuses, but the relation between these effects is unknown. The objective of this study was to determine if mandibular growth retardation was a factor that contributed to induction of cleft palate in C57BL/6J mice. Two doses of MeHg (10 mg/kg maternal body weight) were given subcutaneously on days 10 and 11 of gestation, and the fetuses were morphometrically studied on days 14, 15, and 18. Full clefts of the secondary palate were present in approximately half of the treated day 15 and 18 fetuses; therefore, the cleft palate (CP) and noncleft palate (NCP) groups were analyzed separately to facilitate identification of morphologic changes associated with the clefting. The results showed that, compared with controls, the day 14 MeHg-treated fetuses had significantly smaller placental weights, but only half of the fetuses had delayed palatal shelf elevation, reduced body weight, and delayed morphological development. However on day 15, the CP and the NCP groups had similar reductions in body weight and placental weight. A striking downward and forward positioning of the head was present in the MeHg-treated fetuses with the CP group more severely affected than the NCP group. Significant differences between the three groups (control, NCP, and CP) were present with mean head-to-body angles of 67 degrees, 60 degrees and 51 degrees, respectively. The absence of normal head lifting resulted in a relative mandibular retrognathia that when combined with a decrease in mandibular length produced alterations in spatial relations that were most severe in the CP fetuses. The results suggest that after exposure to MeHg, palatal closure is affected by altered tongue posture associated with the abnormal head positioning and shortening of the mandible that develop following placental and embryonic growth retardation.

Animals↗
PubMed1983

The lidgap defect in mice: update and hypotheses.

The open eye defect in the mouse can result from the action of mutant genes or of teratogens. Among the genetic forms, the lidgap series poses a particular challenge. The lidgap defect appears to be a complex genetic trait and may serve as a model for the genetic analysis of other genetically complex morphological defects in mammals. Extensive breeding data, together with data on the response of the trait to in utero treatment with cortisone, have been analyzed. The results lead us to propose a model involving a single major locus with a series of alleles of graded strength, hypomorphs. The ranking is lg greater than lgstn = lgSt greater than lgM1. The lg/lg genotype alone can be sufficient to produce the lidgap trait, but the "weaker" alleles require a second or even third locus acting in the same pathway. In addition, there is evidence that a recessive suppressor locus is present in the system. These hypotheses are testable and some experiments to develop them further are discussed.

Alleles↗
PubMed1983

Abnormal facial development in the mouse mutant first arch.

The first arch mutation in mice, far, causes specific severe craniofacial defects, different from those caused by other craniofacial mutations. The purpose of the present study was to define the facial defects in far homozygotes, to identify heterozygote expression, if any, and to investigate the embryogenesis of the defect. A genetic study and a developmental study were done. The genetic study showed that only far homozygotes, observed on day 18 of gestation, have cleft palate, pointed snout, and deficiency and disorganized pattern of maxillary vibrissae. Approximately 75% have open eye(s). In addition, only far homozygotes lack infraorbital vibrissa(e) (76%) or have facial skin tags (62%). Thus, the missing infraorbital vibrissa(e) and disturbed maxillary vibrissa pattern could be used to identify far/far embryos for developmental study. The developmental study showed that all of the defects observed in far homozygotes at birth can be accounted for by abnormalities present on day 12 of gestation. Both the palatal shelves and the vibrissal ridges are deficient and irregular. The maxillary branch of the trigeminal nerve is abnormal and associated with a streaming and swirling pattern of mesenchymal cells between vibrissae and palate. No aberrations in cell density are apparent on day 12. The primary defect in the far mutation is not known, but all of the defects derive specifically from the maxillary facial process, one portion of the first branchial arch.

Animals↗
PubMed1982

Differences in frequency of cleft lip among the A strains of mice.

The frequency of spontaneous cleft lip on Day 14 of gestation was examined in the A/J, A/HeJ, A/WySn, A.BY/Sn, A.SW/Sn, B10.A/SgSn, and B10.A(2R)/SgSn inbred strains of mice. A/WySn was found to have a higher frequency of cleft lip (20-30%) than A/J or A/HeJ (10%). Differences among strains in laterality of clefting and in rates of differential mortality of affected embryos were also found. Results of crosses between A/WySn and A/HeJ suggested that the difference in rate of clefting may be due to a genetic maternal effect. The results for A.BY/Sn, A.SW/Sn, B10.A/SgSn and B10.A(2R)/SgSn indicated that no association of cleft lip liability and the H-2 complex was detectable.

Animals↗
PubMed1981

Thyroxin-induced differential mortality of mouse embryos with cleft lip.

Administration of thyroxin in midgestation has been reported to prevent spontaneous cleft lip in term fetuses of genetically predisposed mice. Attempts to repeat this finding have given ambiguous results. The experiment was therefore repeated using CL/Fr and A/HeJ mice, and various thyroxin dosages. The embryos were examined on days 13 and 14, earlier in gestation than in previous studies. The usual complement of cleft-lip embryos, 21% in CL/Fr and 10% in A/HeJ, was present, but they were often dead. At all dosages of thyroxin that caused embryonic mortality, differential mortality of cleft-lip embryos at term after thyroxin treatment is thus due to their increased mortality, not to prevention of the lip defect.

Animals↗
PubMed1980

Genetic maternal effects on cleft lip frequency in A/J and CL/Fr mice.

Two related strains of mice, A/J and CL/Fr, differ in the frequency of spontaneous cleft lip produced in term fetuses: 10% versus 25%. In order to examine the nature of the genetic basis for this difference, various crosses between the strains were made. The results indicated that genes acting in the mothers, rather than in the embryos, caused the strain difference, and that their effect may be on CL(P) embryo survival rather than occurrence. The A/J strain alleles were dominant to those of CL/Fr, and a one-locus difference can explain the data. The importance of genetic maternal effects on CL(P) frequency in mice, with dominance, should be borne in mind when the polygenic, additive threshold model is applied to human data. Neither effect is allowed within the model, yet if the traits are homologous between species, these effects may well be present in man as in the mouse.

Alleles↗
PubMed1980

Genetics of clefting in the mouse.

Whether the relative sensitivity of A/J to CP induction by many teratogens is due to a common mechanism has not been explored beyond cortisone and 6-AN. These latter were found to be probably independent systems. For 6-NA it was suggested that the strain difference was due to three loci with dominance and epistasis and acting in embryos, so that relative liability like that shown by A/J would be derived from simultaneous homozygosity for recessive genes at three loci. The strain difference in CP response to cortisone was explained by two loci with dominance, but with independent effects (no epistasis), and a maternal effect. At least part of the maternal effect and one of the embryonic loci were associated with the H-2 complex.

6-Aminonicotinamide↗
PubMed1977

"Palatal pits"--a new trait in chickens?

During a genetics study of the cleft palate trait in the chicken, another traint, names "Palatal pits" was observed. In the S.C.W. Leghorn inbred line used in the cleft palate study the incidence of palatal pits was 0.79%. Preliminary analysis indicated that the trait was recessive and followed the segregation of a simple Mendelian gene. The symbol pt was suggested to identify this gene.

Animals↗
PubMed1976

Test of the hypothesis that embryonic face shape is a causal factor in genetic predisposition to cleft lip in mice.

It was proposed that embryonic face shape is one of the quantitative variables underlying the threshold trait, cleft lip. To test the hypothesis several facial dimensions were measured in photographs of embryos at an early stage of formation of the face in 3 lines of mice. The lines had been selected from one original population using frequency of cleft lip induced by 6-aminonicotinamide as the selection criterion. Line L was susceptible to spontaneous cleft lip; lines M and C were not. Line L had a significantly smaller distance between the nasal pits than the other 2 lines, but did not differ in overall head size. A trend towards reduced angle between the medial nasal processes in the L line was noted, though this was not statistically significant. These results were predicted by the face-shape hypothesis.

Animals↗
PubMed1975

Genetics of cleft palate in chickens and the relationship between the occurrence of the trait and maternal riboflavin deficiency.

Reciprocal crosses were made between a New Hampshire line of chickens free of cleft palate and affected individuals of a highly inbred S.C.W. Leghorn line having 30 to 50% incidence of cleft palate. The frequency of cleft palate was observed under normal and riboflavin deficient maternal nutrition for the reciprocals of the F1, F2, and backcross to the cleft palate line. Two cases of cleft palate were found in dead embryos of 1368 F1 observations. These may not have represented the genetic trait under study. The response of egg hatchability to riboflavin deficiency was shown to be earlier for cleft palate line hens than for F1 hens, but no maternal effects were found for cleft palate incidence. The frequency of cleft palate in the F2 increased from 0.7% during normal maternal nutrition, to 4.4% during maternal riboflavin deficiency. A similar increase from 8.0% to 12.4% was seen in the backcross progeny. The cleft palate trait was found to be semi-lethal, with mortality associated with severe expression of the trait. No significant sex differences in cleft palate incidence was found in the F2 or backcross generations. The F2 and backcross cleft palate data fit models of genetic control by 3 recessive loci during normal maternal nutrition, and 2 recessive loci during maternal riboflavin deficiency. Penetrance was indicated to be under additive genetic control, and the average was calculated to be between 50 and 75% for all cases. The loss of relevance of one locus during maternal riboflavin deficiency was interpreted to indicate that the homozygous recessive condition at that locus gave disturbed riboflavin metabolism. It was further interpreted to explain the increased occurrence of some traits during teratogenic circumstances as due to the increased probability of obtaining recessive homozygosity at (n - 1) loci compared to (n) loci, and that the role of teratogens in some traits may be in mimicking specific genetic components of the traits.

Animals↗
PubMedDate not supplied

Test of the isoallele hypothesis at the mouse first arch (far) locus.

We tested the hypothesis that differences in wild-type (+) alleles (isoalleles) at the first arch (far) locus between mouse strains ICR/Bc and BALB/cGaBc are responsible for the partially dominant expression of far in the ICR/Bc genetic background, in contrast to its recessive expression in the BALB/cGaBc background. A similar hypothesis concerning isoalleles has been suggested to explain differences in heterozygote expression in some human genetic diseases but appears not to have been tested directly in mammals. First arch is lethal when homozygous. The dominant effects in ICR/Bc mice include defects in mystacial vibrissa pattern formation and cleft palate. To test the isoallele hypothesis, we made the four appropriate genetic crosses between +/far and +/+ mice between strains. The F1 progeny were scored on day 16 of gestation for defective mystacial vibrissa pattern formation and cleft palate. From all four crosses, approximately 30% of F1 fetuses (i.e., 60% of +/far fetuses) had disrupted mystacial vibrissa patterns, and only one fetus had cleft palate. The fact that all crosses produced approximately equal rates of defective progeny disproves the isoallele hypothesis for far. Therefore, differences between strains in alleles at other loci (modifier loci) must cause the differences in heterozygote (+/far) expression. This genetic design can be used for other mutations with strain differences in heterozygote expression to test the importance of isoalleles in mammals.

Alleles↗
PubMedDate not supplied

Mapping the mouse craniofacial mutation first arch (Far) to chromosome 2.

First arch (Far) is a semidominant mutation that causes severe craniofacial defects in mice. Here we report the results of linkage studies with the chromosome 2 markers nonagouti, pallid, and Ulnaless. Far is loosely linked to nonagouti (24-37 cM), more closely linked to pallid (13-28 cM), and closely linked to Ulnaless (2.3 +/- 1.5 cM). The embryological defect in Far mutants is confined to one segmentally-derived region of the head, the anterior first branchial arch. It may therefore be significant that, in mapping near Ulnaless, Far also maps in the vicinity of the Hox-4 gene cluster.

Animals↗
PubMedDate not supplied

Is Far a Hox mutation?

The mouse First arch mutation, Far, causes a severe syndrome of craniofacial defects described previously. All of the known defects are derived from the anterior first arch, and to a very small extent, the dorsal second arch. Recently Far has been shown to be closely linked to Ulnaless on chromosome 2, and therefore in the vicinity of the Hox-4 gene cluster. This paper reports the results of several studies focused on the development origin of the most consistently expressed dominant effect caused by Far, an abnormal major bifurcation of the maxillary nerve. Nerve-stained whole-mount preparations of day 12 embryos showed that in Far mutants the maxillary nerve appears to have a central wedge missing from the normal single-stalked fan shape, and that the nerve defect in Far/Far and +/Far may be equally severe. The effect of retinoic acid on the development of the maxillary nerve was tested. Maternal treatment with 5 mg/kg retinoic acid on day 9 of gestation had no detectable effect on the maxillary nerve of +/Far embryos, and similar treatment with a teratogenic dosage (20 mg/kg) on day 8 or 9 produced no Far-like maxillary nerve defects in genetically normal embryos. The neural crest cells that give rise to nerves and mesenchyme of the first arch originate from specific rhombomeres, discrete segments of the developing head. The rhombomeres of 15 embryos at the 14-23 somite stages, of which 75% are expected to be +/Far or Far/Far, were examined. There was no detectable defect in segmentation or morphology of the rhombomeres compared with controls. The significance of ectopic cartilage in the palate of Far/Far mutants in relation to nerve bifurcation was explored. In histological studies, five out of six Far/Far day-15 fetuses had a rod of ectopic cartilage lateral to the posterior palate, running parallel to, and morphologically similar to, Meckel's cartilage, and lying between the two trunks of the abnormally bifurcated maxillary nerve. None of six +/Far day-15 fetuses examined had detectable ectopic cartilage in this region. We hypothesize that the maxillary nerve defects in Far mutants may be explained by the presence of an ectopic precartilaginous blastema that does not always further develop into detectable cartilage. The ectopic cartilage found in Far/Far resembles the epibranchial cartilage expressed in more posterior branchial arches and in the first arch of lower organisms, and therefore may represent an atavistic posteriorization of the anterior first arch in Far mutants.(ABSTRACT TRUNCATED AT 400 WORDS)

Abnormalities, Multiple↗