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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)

The purpose of this study was to document the extent of disruption in the pattern of palatal rugae caused by the presence of one copy of the First arch mutation. The palatal ruga pattern was found to be disrupted in 86% of 15- to 17-day mouse fetuses that were heterozygous for the First arch mutation in the ICR/Bc strain, compared with 9% in ICR/Bc fetuses of normal (+/+) genotype. This new observation in First arch heterozygotes, together with the previously reported dominant effects of the First arch mutation, particularly the bifurcation of the maxillary nerve (100% in both BALB/cGaBc and ICR/Bc strains), the disruption of maxillary vibrissa pattern (80% in ICR/Bc), and the hemifacial deficiency (38% in ICR/Bc), has led us to redefine the First arch mutation as a semidominant, Far. Like the other defects caused by Far, the rugal defects are in tissue derived from the embryonic maxillary prominence. The rugal defects observed in +/Far palates were always asymmetrical and most often involved fragmentation and misalignment of two or more of rugae 4-7. The relatively large degree of variation in ruga pattern observed in fetuses of normal genotype suggests that it is a less well canalized trait than the normal pattern of maxillary vibrissae which varies only in a few very specific and minor ways. The First arch mutation, which in heterozygotes disrupts pattern formation in both palatal rugae and maxillary vibrissae, can be used to study genetic control of pattern formation in mammalian embryos.

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.

Hemifacial deficiency appeared in 10% of juvenile mice when BALB/cGaBc mice carrying the recessive lethal mutation far were crossed with ICR/Bc. The hemifacial deficiency increased to 15-20% after one backcross to ICR/Bc and then remained at that level for 11 additional generations of backcrossing of far into ICR/Bc. Neither the ICR/Bc strain nor BALB/cGaBc (+/far) produces hemifacial deficiency. Genetic and anatomical studies of adults and fetuses showed that the hemifacial deficiency was due to +/far in the ICR/Bc strain genome; that is, far becomes an incomplete dominant in the ICR/Bc strain background. The hemifacial deficiency (38% of +/far) is probably caused by premature synostosis of the maxilla and premaxilla, observable on day 16 of gestation. An additional 20% of +/far in ICR/Bc have cleft palate and die at birth. Most +/far in both strains have a hidden anomaly, bilateral splitting of the maxillary branch of the trigeminal nerve. far/far homozygotes of both strain backgrounds have a syndrome of severe bilateral deficiency of the derivatives of the maxillary prominence. In human pedigrees, where the equivalents of the dominance modifiers in BALB/cGaBc and ICR/Bc would segregate within families, it would be difficult to recognize that sporadic hemifacial deficiency and severe bilateral maxillary deficiency were due to the same gene. We suggest that human bilateral and unilateral abnormalities of tissue derived from the first branchial arch should be analyzed with the awareness that, in mice, at least, the two kinds of syndrome are due to the same mutant gene.