Journal of craniofacial genetics and developmental biology. Supplement最新文献

Measurements of six reproductive characteristics revealed differences in seven congenic mouse strains with genetic differences in H-2, the major histocompatibility complex (MHC). Associations between reproductive efficiency and MHC has evolutionary implications. One association explains the uneven distribution and heterozygosity of MHC alleles in wild mouse and human populations. The second is based on links between MHC and hormonal sensitivities that regulate an individual's responses to the environment. MHC may be a seat of genotypic-environmental interactions that guide natural selection.

Oral administration of 40-80 mg/d of isotretinoin (13-cis-retinoic acid, Ro 4-3780, Accutane) during the first month of human pregnancy can induce severe congenital malformation. The human Accutane dysmorphic syndrome includes rudimentary external ears, absent or imperforate auditory canals, a triangular microcephalic skull, cleft palate, depressed midface, and anomalies of the brain, jaw, and heart. Children who suffer from this syndrome have large occiputs with narrowing of the frontal bone. Microphthalmia is reported in two cases; notations are made about the orbits in three cases; and the fact that infants could not follow with their eyes is noted in three cases. A decrease in muscle tone is noted in six, cleft palate is present in four, and limb reduction defects are described in two. The cardiac malformations usually include overriding aorta, interrupted or hypoplastic aortic arch, and septation defects of atria and ventricles. There are at least two cases of abnormal origin of the subclavian arteries. Oral isotretinoin in the pregnant hamster also induces similar congenital malformations. A human case of isotretinoin-induced dysmorphia is presented and compared with other affected infants and affected hamsters. The metabolic fate and pharmacokinetic parameters of isotretinoin in humans and rodents are discussed in relation to the teratogenic response. The results suggest that humans are approximately 16 times more sensitive to the teratogenic effects of oral isotretinoin than are hamsters.

Twenty-three puppies with cranofacial and limb abnormalities from a family of Australian shepherd dogs were studied anatomically. Limb abnormalities included lumbar scoliosis, short malformed tibias and fibulas, and polydactyly. Craniofacial abnormalities consisted of retronathia, cleft palate, and cleft lip. The clefts can be separated into three categories: group I, cleft of the secondary palate associated with a midline cleft lip; group II, unilateral cleft of the lip and primary and secondary palate; and group III, complete bilateral cleft of the lip and primary and secondary palate. Comparing human clefts with the canine clefts suggests that the development of the secondary palate is similar whereas the development of the upper lip is different. In the dog, the maxillary processes fuse in the midline to produce the majority of the upper lip, whereas in the human the upper lip is composed of fused maxillary and medial nasal processes.

The relationship between dexamethasone (DEX)-induced phosphatidylinositol (PI) turnover and inhibition of cell proliferation was investigated in human embryonic palatal mesenchyme (HEPM) cells in culture. Evidence based on studies with the partial glucocorticoid agonist cortexolone suggests both the PI response and the inhibition of proliferation are mediated by the glucocorticoid receptor. The role of PI turnover in the mechanism of DEX-inhibited HEPM cell proliferation was investigated using two agents that stimulated PI turnover (serum and platelet-derived growth factor) and one that did not stimulate PI turnover (epidermal growth factor). DEX partially inhibited both serum-induced and platelet-derived growth factor-induced proliferation of HEPM but not epidermal growth factor-induced proliferation. These results suggest that DEX-induced alteration of PI metabolism may be involved in the mechanism by which DEX inhibits proliferation of cultured HEPM cells and results in cleft palate formation in rodents.

Neural crest mesenchyme participates in the formation of craniofacial structures that are malformed in the fetal alcohol syndrome (FAS). We studied the effects of continuous ethanol treatment (0.05%, 0.10%, 0.15%, 0.20%) on developing neural crest cells in vitro. These cells migrate, but many fail to develop their usual arborized dendrites. Exposure of well differentiated dendritically arborized cells to ethanol only on day 6 for 2 hr and 20 min results in rapid cell retraction and alteration in cell-to-cell contacts. Longer treatment causes loss of substratum adhesion. Monoclonal antibodies against tubulin and actin reveal that these ethanol-induced morphological changes are related to disruption of microtubules and microfilaments. Thus ethanol may exert at least part of its teratogenic effect by interferring with the structure and function of the cytoskeleton.

Three mesenchymal tissues participate in the formation of orofacial tissues; these are the neural crest, paraxial mesoderm, and lateral mesoderm. Interactions both among these populations and between them and surrounding epithelial tissues are an essential feature of facial development. Perturbation of these interactions may result in craniofacial malformations and dysmorphologies. This review outlines the origins and early morphogenetic movements of each of the three mesenchymal populations, then describes experiments which reveal some of the interactions that control their development. Spatial organization within cephalic mesenchyme is manifest initially in connective tissue precursors. In the facial region these are derived from the neural crest; in contrast, much of the neurocranium is derived from paraxial mesoderm. Most crest populations become spatially programmed prior to their emergence from the neuroepithelium, presumably during the primary induction of the neural plate. As they migrate to form the branchial arches, the crest populations bring spatial information to these peripheral regions. Connective tissue-forming populations within cephalic paraxial mesoderm display a similar inherent spatial programming, but it is not known when or how they acquire this information.

The major gene that causes cleft lip in the A/WySn mouse strain is being transferred to the unrelated normal AEJ/GnRk strain background by the backcross-testcross method. The result, a congenic strain pair differing only at the major cleft lip locus and closely linked loci, will allow the unequivocal identification of the genetic lesion that causes cleft lip. Four backcross generations have been completed, and the background geneotype is calculated to be 97% of AEJ/GnRk origin. The recovery of the cleft lip trait in testcrosses of each generation is compatible with the expected values for the transfer of a single major gene with 8% penetrance. Multilocus inheritance beyond two loci is ruled out. In separate experiments using mostly Robertsonian chromosomes as markers of the normal allele at the cleft lip locus, portions of the genome have been screened for the map location of the cleft lip gene. The gene is probably not within 10-20 cM of the centromere of 12 different identified autosomal chromosomes nor linked to Ph on chromosome 5. Previous studies have suggested that the cleft lip gene is not linked to c (chromosome 7), b (chromosome 4), d (chromosome 9), T, H-2 (chromosome 17), or N (chromosome 15).

While many studies have demonstrated sexual dimorphism and racial variation (Mongoloid greater than Caucasian greater than Black) in the incidence of palatal clefting, only generalized statements have been made concerning the causal mechanism (eg, "genetic propensity"). The present study tests the hypothesis that the more rapid the growth rate of the width of the facial skeleton, the higher the incidence of palatal clefting, given a uniform environmental insult. Two strains of pregnant rats with differing rates of craniofacial development (Wistar-fast and Sprague-Dawley-slow) were injected prenatally with high doses of vitamin A (300,000 IU/kg) on days 10-13 gestation. Fetuses were examined at 20 d prenatally and the incidence of palatal clefting was recorded. A significantly higher (P less than .05) incidence of palatal clefting was noted in the more rapidly developing strain (66% vs 81%). These results support statements by Fraser and others who suggest that head width and palatal clefting are causally related. The "genetic propensity" in this case, then, is the rate of palatal width development.

The contact sites between the medial and lateral nasal processes during the period of facial formation of the mouse embryo were examined by light and electron microscopy. Characteristic superficial cells were observed at the transitional regions between the surface ectoderms and the nasal epithelia at the end of the isthmus, where the initial contact of the opposing nasal processes took place. At the later stage the contact sites extended to the bottom of the ravine formed by the two nasal processes, where the superficial cells always seemed to bridge the area between the nasal processes. These superficial cells had a large, clear nucleus and abundant cytoplasm as well as the common structural features characteristic of the embryonic cells. These cells were also observed on the surface near the contact site in the presumptive fusion area. These observations suggest that these superficial cells play a critical role in the epithelial adhesion of the medial and lateral nasal processes throughout the fusion.

Despite nearly half a century of intensive investigation, the etiology of non-syndromic cleft lip with or without cleft palate (CL +/- P) remains unknown because most studies have been descriptive rather than analytic. This study summarizes rigorous analyses of CL +/- P in the families of non-syndromic, CL +/- P surgical probands from three populations: Denmark, London, England, and Shanghai, China. Three main conclusions could be drawn from the results. The data provide no support for the multifactorial threshold model summarized by Carter (1976) and most often proposed to explain the etiology of CL +/- P. Each dataset provides evidence that there may be a major gene for liability to CL +/- P in at least a portion of cases. The data are consistent with possible genetic heterogeneity in CL +/- P.