Biomedical subjects
M Melnick
Publications and source records attributed to M Melnick.
Articulation implications in a case of anhidrotic ectodermal dysplasia and partial anodontia.
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The CORT-GR signal transduction pathway and CORT-induced cleft palate in H-2 congenic mice.
A significant association between genes at or near the H-2 complex and glucocorticoid (CORT)-induced cleft palate in mice has been conclusively demonstrated. In addition, the frequency of CORT-induced cleft palate in heterozygous offspring from reciprocal crosses has been shown to be dependent on maternal H-2 haplotype. Although CORT responses are known to be mediated through the glucocorticoid receptor (GR), the involvement of H-2 haplotype-specific variation in the embryonic CORT-GR signal transduction pathway in CORT responsiveness remains uncertain. In this study, we characterized the embryonic (E13 to E15) CORT-GR pathway in developing B10 (H-2b) and B10.A (H-2a) mouse palates. Northern analysis demonstrates similar GR transcripts and mRNA steady-state levels in embryonic B10 and B10.A mouse palates. Palatal GR M(r) and pI, as determined by Western analysis, are similar between strains and among gestational days. We also analyzed possible haplotype-specific qualitative or quantitative differences in the ability of the GR to bind a glucocorticoid response element (GRE); no significant differences in the GR-GRE complex or in the levels of activated GR are seen between strains or among gestational days. Based on these results, we conclude that H-2 associated differences in susceptibility to CORT-induced cleft palate are not associated with either variation in embryonic GR or increasing gestational age. To determine if endogenous differences in maternal circulating corticosterone levels are related to differential embryonic CORT responsiveness, the levels of serum corticosterone were determined by RIA in pregnant dams on day 13 of gestation.(ABSTRACT TRUNCATED AT 250 WORDS)
Glucocorticoids, TGF-beta, and embryonic mouse salivary gland morphogenesis.
Branching morphogenesis is a fundamental embryologic process in many developing organs: salivary gland, lung, pancreas, mammary gland, and kidney. Glucocorticoids (CORT) are known to regulate morphogenesis in several branching organs (e.g., lung); we hypothesize that CORT is also important to embryonic mouse salivary gland morphogenesis. We studied the CORT-glucocorticoid receptor (GR) signal transduction pathway during embryonic mouse submandibular gland development. Western analysis demonstrates that the 96-kDa GR is present in E14 to E18 submandibular glands. The embryonic GR is functional, as defined by its ability to bind a DNA CORT response element, for all gestational ages evaluated (E14 to E18); increasing GR levels are observed with progressive development. The level of endogenous corticosterone in embryonic submandibular glands was also determined. Using radioimmunoassays corticosterone is first detected on day 15 of gestation; there is a progressive increase in steroid levels from day 15 to 18 of gestation. In addition, we investigated the effect of exogenous CORT on submandibular gland morphogenesis in vivo and in vitro. In vivo experiments were performed using maternal injection of CORT or sham injection on day 12 of gestation with sacrifice 72 hr post-injection (E15). CORT treatment significantly increases embryonic submandibular gland growth in vivo. To further analyze the effect of exogenous CORT on embryonic submandibular gland morphogenesis, E13 mouse submandibular glands were cultured under serum-free, chemically-defined conditions. A significant (P < 0.05) enhancement of mean branching ratios (72 hr/0 hr) is detected in CORT-supplemented explants (10(-5) M to 10(-8) M) compared to control explants; doses more dilute than 10(-8) M CORT do not significantly (P > 0.10) increase the induction of branching. In addition, CORT administration to embryonic mice in utero enhances the expression of acinar-cell-specific mucin protein. These data indicate that the CORT-GR signal transduction pathway plays an important role in salivary gland morphogenesis. Northern analysis of TGF-beta 1, TGF-beta 2, and TGF-beta 3 transcript levels in vivo confirms the presence of TGF-beta 1 and TGF-beta 2 and identifies TGF-beta 3 in embryonic submandibular glands. To begin to identify a molecular mechanism of CORT-GR mediated submandibular gland morphodifferentiation, we studied the effect of CORT on growth factor gene expression, specifically TGF-beta. Northern analysis suggests that the CORT-GR signal transduction pathway modulates the rate of morphogenesis by regulating TGF-beta 2 and TGF-beta 3 mRNA expression.
Cleft lip and palate etiology and its meaning in early 20th century England: Galton/Pearson vs. Bateson; polygenically poor protoplasm vs. Mendelism.
At the outset of the 20th century in England there arose a venomous dispute between Mendelian geneticists such as Bateson and anti-Mendelian biometricians such as Pearson over the genetic etiology of such "physical deformities" as cleft lip and palate. To Pearson et al., such traits were an expression of physical and racial degeneracy which could be traced to polygenically poor protoplasm. To Bateson et al., such traits were Mendelian unit characters whose segregation could be seen in carefully constructed family pedigrees. Bateson dismissed the work of the anti-Mendelians as "unsound in construction" and predicted such thinking would inevitably lead to "brutal" control of those the larger society deemed unfit. History proved Bateson astutely prescient.
Association between non-right-handedness and cleft lip with or without cleft palate in a Chinese population.
The etiology of non-syndromic cleft lip with or without cleft palate (CL +/- P) is unclear, although both familial and environmental factors are implicated. Because CL +/- P occurs at approximately the time of brain lateralization and is most often unilateral, developmental asymmetry effects have been postulated in CL +/- P etiology. Handedness is frequently used as an indicator of brain lateralization; therefore, several studies have examined the relationship between cleft laterality and handedness. However, these studies have had conflicting results. The present study investigated handedness in a Chinese sample of 211 non-syndromic CL +/- P surgical probands (ascertained in Shanghai for family studies of CL +/- P), 221 population-based but unmatched controls, and 272 first-degree relatives of the probands. Handedness was assessed by means of laterality quotients (LQ) calculated from questionnaire data. Mean LQ's were compared, as were various arbitrary definitions of handedness based on the LQ, for cases versus controls, males versus females, right-sided versus left-sided clefts, and cleft lip alone versus cleft lip plus cleft palate. CL +/- P cases had a significantly higher proportion of non-right-handedness (NRH) than controls, regardless of the definition of NRH (P values < or = .001). There were no statistically significant differences for any of the other comparisons. Familiarity of NRH was tested by comparing first-degree relatives of cases to controls; first-degree relatives were found to have a significantly higher proportion of NRH than controls, supporting familial effects in NRH. These results support the concept of a common etiology and/or developmental pathway for CL +/- P and handedness.