Oral clefts and vitamin supplementation

Objectives: the evidence linking low levels of folic acid and orofacial clefting (OFC) is presently equivocal, There is stronger evidence for the role of folic acid supplementation in protection against the occurrence and recurrence of neural tube defects. The present investigation tested the hypotheses that cleft lip, cleft palate, or both are inversely associated with maternal intake of dietary and supplemental vitamins during the periconceptional period and first 4 months of pregnancy in a Brazilian population.Design: A population-based, case-control study of cleft lip with or without cleft palate (CL(P)) and isolated cleft palate (CP) in a Brazilian population. in structured interviews, case histories were taken from the mothers of a consecutive sample of 450 infants born with nonsyndromic OFC,Results: Mothers who had children with CL(P) were less likely to have been supplemented during the periconceptional period. The statistical significance of the difference in prevalence of the use of supplements between mothers of patients and of controls was greater for the CL(P) group: p < .05 for CP and p < .001 for CL(P). Multivariate analysis confirmed this finding of a protective effect for both types of orofacial cleft,Conclusions: the use of vitamin supplements in the first 4 months of pregnancy was suggestive of a protective effect against the occurrence of CP and CL(P) in this population, the significance of an association between multivitamin supplementation and OFC and the possible role of gene/environment interaction are discussed.

Structural and ultrastructural characterization of the embryonic development of Pseudoplatystoma spp. hybrids

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Incidência de malformações congênitas em crianças concebidas através de injeção intracitoplasmática de espermatozóides

Purpose: to evaluate the incidence and types of major congenital malformations (MCM) in liveborn children conceived by intracytoplasmic sperm injection (ICSI). Methods: a total of 680 liveborn children resulted from 511 couples submitted to ICSI from January, 1999 to December, 2002. Data collection of the children was performed through standardized questionnaire and clinical examination. Of the 511 couples, 366 had been contacted for a sampling of 371 gestations. Of the 680 liveborn, 520 had been evaluated, 250 of them (48.1%) through questionnaire and 270 (51.9%) through questionnaire and physical examination. Two hundred and fifty children were from singleton pregnancies and 270 from multiple pregnancies. Malformations were classified according to the 10th revision of the International Statistical Classification of Diseases and Related Health. Only MCM were analyzed in this study. The incidence of MCM was compared with that of the general population obtained by the Latin American Collaborative Study of Congenital Malformations. The statistical analysis was performed by the χ 2 test (level of significance p<0.05). Results: of the 520 children, 15 presented MCM, resulting in an incidence of 2.9%. There was no difference in relation to the control group (p>0.05), which showed 2.6% incidence of MCM. The most frequent malformations were of cardiac origin (four isolated and two associated), corresponding to 40% of the total. The other types of MCM were: renal (three), neural tube (two), skull (one), cleft lip (one), genital (one), Down syndrome (associated with cardiac malformations) (two), and musculoskeletal (one). Six MCM occurred in children from singleton pregnancies and nine in children from multiple pregnancies. Conclusion: the liveborn children conceived by ICSI presented incidence of major congenital malformations (2.9%) near to the expected for the general population (2.6%). However, to establish the risks of MCM with precision it is necessary to continue the evaluation of the children conceived by ICSI.

Birth defects in newborns and stillborns: An example of the Brazilian reality

Background: This study constitutes a clinical and genetic study of all newborn and stillborn infants with birth defects seen in a period of one year in a medical school hospital located in Brazil. The aims of this study were to estimate the incidence, causes and consequences of the defects. Methods. For all infants we carried out physical assessment, photographic records, analysis of medical records and collection of additional information with the family, besides the karyotypic analysis or molecular tests in indicated cases. Result: The incidence of birth defects was 2.8%. Among them, the etiology was identified in 73.6% (ci95%: 64.4-81.6%). Etiology involving the participation of genetic factors single or associated with environmental factors) was more frequent 94.5%, ci95%: 88.5-98.0%) than those caused exclusively by environmental factors (alcohol in and gestational diabetes mellitus). The conclusive or presumed diagnosis was possible in 85% of the cases. Among them, the isolated congenital heart disease (9.5%) and Down syndrome (9.5%) were the most common, followed by gastroschisis (8.4%), neural tube defects (7.4%) and clubfoot (5.3%). Maternal age, parental consanguinity, exposure to teratogenic agents and family susceptibility were some of the identified risk factors. The most common observed consequences were prolonged hospital stays and death. Conclusions: The current incidence of birth defects among newborns and stillbirths of in our population is similar to those obtained by other studies performed in Brazil and in other underdeveloped countries. Birth defects are one of the major causes leading to lost years of potential life. The study of birth defects in underdeveloped countries should continue. The identification of incidence, risk factors and consequences are essential for planning preventive measures and effective treatments. © 2011 Fett-Conte et al; licensee BioMed Central Ltd.

Avaliação da exposição ao mercúrio e seus compostos em mães e seus recém-nascidos em Porto Velho - RO

Foram estudados 103 binômios mãe-filho nascidos em hospitais da cidade de Porto Velho-RO, durante os meses de novembro/2000 até fevereiro/2001. Foram analisadas amostras de cabelo da mãe e do recém-nascido, sangue materno, placenta e cordão umbilical. As coletas das amostras foram realizadas no momento do parto. Aplicou-se questionário a mãe onde se registrou informações relevantes para o risco de contaminação mercurial e/ou malformações. Os produtos da gestação que apresentaram malformação foram incluídos no estudo. A medida da exposição ao Metilmercúrio foi feita utilizando os biomarcadores coletados e realização de técnicas através do método de espectofotometria de absorção atômica pelo vapor frio. Utilizou-se o fator prático de conversão total em mercúrio que é de 0,90 a 0,92. Após análise e estudo estatístico as principais conclusões foram: o consumo de bebida alcoólica durante a gravidez, dentre outras variáveis, não influenciou no aparecimento de malformações, especialmente os defeitos do tubo neural (DNT) a maioria das malformações encontradas foi DNT (66,6%) que foram significativamente correlacionadas com os níveis de mercúrio total no cabelo do recém-nascido; os níveis de mercúrio total na placenta e no cordão umbilical foram equivalentes.

Immunolocalization of myosin Va in the developing nervous system of embryonic chicks

Myosins are molecular motors associated with the actin cytoskeleton that participate in the mechanisms of cellular motility. During the development of the nervous system, migration of nerve cells to specific sites, extension of growth cones, and axonal transport are dramatic manifestations of cellular motility. We demonstrate, via immunoblots, the expression of myosin Va during early stages of embryonic development in chicks, extending from the blastocyst period to the beginning of the fetal period. The expression of myosin Va in specific regions and cellular structures of the nervous system during these early stages was determined by immunocytochemistry using a polyclonal antibody. Whole mounts of chick embryos at 24-30-h stages showed intense immunoreactivity of the neural tube in formation along its full extent. Cross-sections at these stages of development showed strong labeling in neuroepithelial cells at the basal and apical regions of the neural tube wall. Embryos at more advanced periods of development (48h and 72 h) showed distinctive immunolabeling of neuroepithelial cells, neuroblasts and their cytoplasmic extensions in the mantle layer of the stratified neural tube wall, and neuroblasts and their cytoplasmic extensions in the internal wall of the optic cup, as well as a striking labeling of cells in the apparent nuclei of cranial nerves and budding fibers. These immunolocalization studies indicate temporal and site-specific expression of myosin Va during chick embryo development, suggesting that myosin Va expression is related to recruitment for specific cellular tasks.

Polymorphism C1420T of Serine hydroxymethyltransferase gene on maternal risk for Down syndrome

Recent researches have investigated the factors that determine the maternal risk for Down syndrome (DS) in young woman. In this context, some studies have demonstrated the association between polymorphisms in genes involved on folate metabolism and the maternal risk for DS. These polymorphisms may result in abnormal folate metabolism and methyl deficiency, which is associated with aberrant chromosome segregation leading to trisomy 21. In this study, we analyzed the influence of the polymorphism C1420T in Serine hydroxymethyltransferase (SHMT) gene on maternal risk for DS and on metabolites concentrations of the folate pathway (serum folate and plasma homocysteine and methylmalonic acid). The study group was composed by 105 mothers with DS children (case group) and 185 mothers who had no children with DS (control group). The genotype distribution did not show significant statistical difference between case and control mothers (P = 0.24) however a protective effect between genotypes CC (P = 0.0002) and CT (P < 0.0001) and maternal risk for DS was observed. Furthermore, the SHMT C1420T polymorphism (rs1979277) does not affect the concentration of metabolites of folate pathway in our DS mothers. In conclusion, our data showed a protective role for the genotypes SHMT CC and CT on maternal risk for DS. The concentrations of metabolites of folate pathway did not differ significantly between the genotypes SHMT.

RGMa and RGMb expression pattern during chicken development suggest unexpected roles for these repulsive guidance molecules in notochord formation, somitogenesis, and myogenesis

Background: Repulsive guidance molecules (RGM) are high-affinity ligands for the Netrin receptor Neogenin, and they are crucial for nervous system development including neural tube closure; neuronal and neural crest cell differentiation and axon guidance. Recent studies implicated RGM molecules in bone morphogenetic protein signaling, which regulates a variety of developmental processes. Moreover, a role for RGMc in iron metabolism has been established. This suggests that RGM molecules may play important roles in non-neural tissues. Results: To explore which tissues and processed may be regulated by RGM molecules, we systematically investigated the expression of RGMa and RGMb, the only RGM molecules currently known for avians, in the chicken embryo. Conclusions: Our study suggests so far unknown roles of RGM molecules in notochord, somite and skeletal muscle development. Developmental Dynamics, 2012. (C) 2012 Wiley Periodicals, Inc.

Genetic polymorphisms modulate the folate metabolism of Brazilian individuals with Down syndrome

Individuals with Down syndrome (DS) carry three copies of the Cystathionine beta-synthase (C beta S) gene. The increase in the dosage of this gene results in an altered profile of metabolites involved in the folate pathway, including reduced homocysteine (Hcy), methionine, S-adenosylhomocysteine (SAH) and S-adenosylmethionine (SAM). Furthermore, previous studies in individuals with DS have shown that genetic variants in genes involved in the folate pathway influence the concentrations of this metabolism's products. The purpose of this study is to investigate whether polymorphisms in genes involved in folate metabolism affect the plasma concentrations of Hcy and methylmalonic acid (MMA) along with the concentration of serum folate in individuals with DS. Twelve genetic polymorphisms were investigated in 90 individuals with DS (median age 1.29 years, range 0.07-30.35 years; 49 male and 41 female). Genotyping for the polymorphisms was performed either by polymerase chain reaction (PCR) based techniques or by direct sequencing. Plasma concentrations of Hcy and MMA were measured by liquid chromatography-tandem mass spectrometry as previously described, and serum folate was quantified using a competitive immunoassay. Our results indicate that the MTHFR C677T, MTR A2756G, TC2 C776G and BHMT G742A polymorphisms along with MMA concentration are predictors of Hcy concentration. They also show that age and Hcy concentration are predictors of MMA concentration. These findings could help to understand how genetic variation impacts folate metabolism and what metabolic consequences these variants have in individuals with trisomy 21.

Oral cleft prevention program (OCPP)

Background Oral clefts are one of the most common birth defects with significant medical, psychosocial, and economic ramifications. Oral clefts have a complex etiology with genetic and environmental risk factors. There are suggestive results for decreased risks of cleft occurrence and recurrence with folic acid supplements taken at preconception and during pregnancy with a stronger evidence for higher than lower doses in preventing recurrence. Yet previous studies have suffered from considerable design limitations particularly non-randomization into treatment. There is also well-documented effectiveness for folic acid in preventing neural tube defect occurrence at 0.4 mg and recurrence with 4 mg. Given the substantial burden of clefting on the individual and the family and the supportive data for the effectiveness of folic acid supplementation as well as its low cost, a randomized clinical trial of the effectiveness of high versus low dose folic acid for prevention of cleft recurrence is warranted. Methods/design This study will assess the effect of 4 mg and 0.4 mg doses of folic acid, taken on a daily basis during preconception and up to 3 months of pregnancy by women who are at risk of having a child with nonsyndromic cleft lip with/without palate (NSCL/P), on the recurrence of NSCL/P. The total sample will include about 6,000 women (that either have NSCL/P or that have at least one child with NSCL/P) randomly assigned to the 4 mg and the 0.4 mg folic acid study groups. The study will also compare the recurrence rates of NSCL/P in the total sample of subjects, as well as the two study groups (4mg, 0.4 mg) to that of a historical control group. The study has been approved by IRBs (ethics committees) of all involved sites. Results will be disseminated through publications and presentations at scientific meetings. Discussion The costs related to oral clefts are high, including long term psychological and socio-economic effects. This study provides an opportunity for huge savings in not only money but the overall quality of life. This may help establish more specific clinical guidelines for oral cleft prevention so that the intervention can be better tailored for at-risk women. ClinicalTrials.gov Identifier NCT00397917

Birth defects in newborns and stillborns: an example of the Brazilian reality

Abstract Background This study constitutes a clinical and genetic study of all newborn and stillborn infants with birth defects seen in a period of one year in a medical school hospital located in Brazil. The aims of this study were to estimate the incidence, causes and consequences of the defects. Methods For all infants we carried out physical assessment, photographic records, analysis of medical records and collection of additional information with the family, besides the karyotypic analysis or molecular tests in indicated cases. Result The incidence of birth defects was 2.8%. Among them, the etiology was identified in 73.6% (ci95%: 64.4-81.6%). Etiology involving the participation of genetic factors single or associated with environmental factors) was more frequent 94.5%, ci95%: 88.5-98.0%) than those caused exclusively by environmental factors (alcohol in and gestational diabetes mellitus). The conclusive or presumed diagnosis was possible in 85% of the cases. Among them, the isolated congenital heart disease (9.5%) and Down syndrome (9.5%) were the most common, followed by gastroschisis (8.4%), neural tube defects (7.4%) and clubfoot (5.3%). Maternal age, parental consanguinity, exposure to teratogenic agents and family susceptibility were some of the identified risk factors. The most common observed consequences were prolonged hospital stays and death. Conclusions The current incidence of birth defects among newborns and stillbirths of in our population is similar to those obtained by other studies performed in Brazil and in other underdeveloped countries. Birth defects are one of the major causes leading to lost years of potential life. The study of birth defects in underdeveloped countries should continue. The identification of incidence, risk factors and consequences are essential for planning preventive measures and effective treatments.

Impiego della spettrometria di massa nell'analisi di fumonisine in alimenti e matrici di origine animale

Mycotoxins are heterogeneous chemical compounds characterized by a low molecular weight and synthesized by the secondary metabolism of different molds. Fumonisins are water-soluble mycotoxins produced by Fusarium species spoiling corn and derived produc ts. These mycotoxins can be a health hazard when consuming contaminated cereals, but they can reach humans also indirectly through the consumption of food products derived from animals fed with contaminated feed. Fumonisins have been associated with several animal and human diseases: they are suspected risk factors for esophageal and liver cancers, neural tube defects and cardiovascular problems. Improved methods are needed to accurately assess fumonisins concentrations in food of vegetable and animal origin, in order to prevent acute and chronic human exposure. The aim of the present work was to evaluate the versatility and the performances of mass spectrometry, coupled with liquid chromatography, in fumonisins analysis from foods and matrices of animal origin. Different methods for the identification and quantification of fumonisins and related products have been developed and validated to determine fumonisin B1 in milk, fumonisin B1, fumonisin B2 and their complete hydrolyzed products (HFB1 and HFB2) in pig liver and fumonisins B1 and B2 in complete and complementary dry dog food. The experimental procedures have been carefully studied, considering matrices features, number and type of molecules to detect. Therefore, several extraction, clean up and separation techniques were tested in order to obtain the better conditions of sample processing. The fit for purpose sample preparation, matched with high mass spectrometry sensibility and specificity, have allowed to achieve good results in any tested animal matrices. Hence, the developed methods were validated and have shown a high accuracy, sensibility and precision, fulfilling performance requirements of Decision 2002/657/EC and of European Project Standard, Measuring and Testing (SMT). In any developed method, the analytes were identified and quantified even at very low concentrations : the limits of quantification resulted lower than other similar works, performed with different detectors. These methods were applied to some commercial samples and to some samples collected for research projects in the Department of Veterinary Public Health and Animal Pathology (DVPHAP) of University of Bologna. Although the disclosed data must be considered completely preliminary and without statistical significance, they emphasize the presence of mycotoxins in animal products. The outcomes obtained from the processed samples (bovine milk, pig liver and dry dog food) suggest the efficacy of these methods also on other food matrices, confirming the versatility and the performances of mass spectrometry, coupled with liquid chromatography, in fumonisins analysis. Moreover the results underline the need to set up a large scale monitoring in order to evaluate the presence of fumonisins in food of animal origin for human consumption.

Evidenza del coinvolgimento di geni nell'insorgenza delle schisi labio-palatine

The CL/P are the most common and easily recognizable craniofacial malformations with a complex etiology that requires the involvement of genetic and environmental components. The analysis of the genetic component shows more than 14 loci and genes involved in the onset of the disease. I’ve selected and investigated some of the possible candidate genes for CL/P. MYH14 gene, that maps on chromosome 19, on the OFC3 locus, and shows a strong homology with MYH9 gene. I’ve also investigated TP63 and MID1 genes, that are responsible respectively for EEC syndrome and Opitz syndrome, both of them presenting cleft. I’ve also decided to investigate JAG2 because TP63 product regulates the this gene, and both of them are component of the Notch signalling pathway. I’ve, also, studied the MKX and LMO4 genes. MKX is an important development regulator that is highly expressed in palatal mesenchyme, and map in the region responsible for Twirler mutation that cause cleft in mouse. LMO4 is necessary for neural tube development and cooperating with Grhl3, promotes cellular migration during morphogenetic events like “in utero” cleft healing. Low folate levels and high levels of homocysteine increase the risk of cleft, genes involved in their metabolism may be of interest in cleft occurrence. I’ve decided to investigate BHMT and CBS genes coding for enzymes involved in homocysteine metabolism. I’ve also investigated BHMT2 gene that maps close to BHMT and presents with him a 73% of homology. I’ve performed a linkage analysis using SNPs mapping in the genes and their boundaries, for each gene, for MKX and LMO4 I’ve also performed a sequencing analysis. My results for MID1 and CBS genes support the hypothesis of a possible role of these genes in cleft. I’ve found borderline association values for JAG2, MKX and LMO4 genes.

Untersuchungen zur Funktion und Regulation der Rezeptor-Tyrosin-Phosphatase RPTPlambda bei der Entwicklung des Mittel- und Hinterhirns

Der isthmische Organisator liegt an der Grenze zwischen dem sich entwickelnden Mittel- und Hinterhirn und kontrolliert Wachstum und Musterbildung dieser beiden Hirnregionen. In der vorliegenden Arbeit wird die räumliche und zeitliche Expression der Rezeptor-ähnlichen Protein Tyrosin Phosphatase lambda aus dem Huhn (cRPTPλ, auch als cRPTPψ bekannt) während der Entwicklung dieser Struktur beschrieben. Nach einer anfänglich weitläufigen Expression im kaudalen Vorderhirn und in der Mittelhirnregion, beschränkt sich die Expression von cRPTPλ zwischen dem embryonalen Tag E2 und E3.5 auf die ventrale Mittellinie des Neuralrohrs, den Bereich der späteren neuralen Retina und Linse und auf einen schmalen Ring anterior der isthmischen Einschnürung, welcher der molekularen Mittel- / Hinterhirngrenze (MHO) entspricht. Ab dem embryonalen Tag E3.5 wird RPTPλ dann auch im gesamten Mittelhirn gebildet. Um Hinweise auf die Funktion von cRPTPλ zu bekommen, wurde die Regulation dieses Moleküls untersucht. Die Expression von cRPTPλ am MHO wird von dem Fibroblasten Wachstumsfaktor Fgf8 und dem Transkriptionsfaktor Lmx1b, nicht aber von dem sezernierten Glykoprotein Wnt1 induziert. Der Transkriptionsfaktor En-1 unterdrückt die Expression von cRPTPλ am MHO. cRPTPλ-Expression im Mittelhirn wird negativ durch das sezernierte Protein Sonic Hedgehog reguliert, während Lmx1b und En-1 dort keinen Einfluss auf das Expressionsmuster von cRPTPλ haben. Fgf8 und Wnt1 sind maßgeblich an der Regulation von Wachstum und Musterbildung des embryonalen Mittelhirns beteiligt. Funktionelle Studien zu RPTPλ deuten darauf hin, dass dieses Protein als negativer Rückkopplungsmechanismus beider Signalwege wirken kann. RNAi- und Überexpressionsstudien am MHO lieferten Hinweise darauf, dass RPTPλ der Induktion der Wnt1-Expression durch Fgf8 entgegenwirkt. Dies scheint durch Interaktion noch unbekannter Faktoren mit der Juxtamembrandomäne von RPTPλ vermittelt zu werden. Auf das Expressionsmuster von Fgf8 selbst, oder einer Reihe anderer Faktoren, die ebenfalls von Fgf8 reguliert werden, hat RPTPλ allerdings keinen Einfluss. Des Weiteren konnte in dieser Arbeit gezeigt werden, dass eine „künstliche“ Aufrechterhaltung der Expression von cRPTPλ im Mittelhirn zwischen dem embryonalen Tag E2 und E3.5 zu einem stark verkleinerten Mesenzephalon führt. RPTPλ bindet in vivo an β-Catenin, ein zentrales Protein des kanonischen Wnt-Signalweges, und moduliert dadurch vermutlich das Wnt-Signal, welches seinerseits Proliferation im Mesenzephalon fördert. Durch diesen Mechanismus könnte cRPTPλ als „Bremse“ des kanonischen Wnt-Signalweges im Mittelhirn wirken.

Genetische Mechanismen der dorsoventralen Musterbildung im embryonalen Gehirn von Drosophila

In Vertebraten und Insekten ist während der frühen Entwicklung des zentralen Nervensystems (ZNS), welches sich aus dem Gehirn und dem ventralen Nervensystem (VNS) zusammensetzt, die Unterteilung des Neuroektoderms (NE) in diskrete Genexpressions-Domänen entscheidend für die korrekte Spezifizierung neuraler Stammzellen. In Drosophila wird die Identität dieser Stammzellen (Neuroblasten, NB) festgelegt durch die positionellen Informationen, welche von den Produkten früher Musterbildungsgene bereitgestellt werden und das Neuroektoderm in anteroposteriorer (AP) und dorsoventraler (DV) Achse unterteilen. Die molekulargenetischen Mechanismen, welche der DV-Regionalisierung zugrunde liegen, wurden ausführlich im embryonalen VNS untersucht, sind für das Gehirn jedoch weitestgehend unverstanden. rnIm Rahmen dieser Arbeit wurden neue Erkenntnisse bezüglich der genetischen Mechanismen gewonnen, welche die frühembryonale Anlage des Gehirns in DV-Achse unterteilen. So konnte gezeigt werden, dass das cephale Lückengen empty spiracles (ems), das Segmentpolaritätsgen engrailed (en), sowie der „Epidermal growth factor receptor“ (EGFR) und das Gen Nk6 homeobox (Nkx6) für Faktoren codieren, die als zentrale Regulatoren die DV Musterbildung in der Gehirnanlage kontrollieren. Diese Faktoren interagieren zusammen mit den ebenso evolutionär konservierten Homöobox-Genen ventral nervous system defective (vnd), intermediate neuroblasts defective (ind) und muscle segment homeobox (msh) in einem komplexen, regulatorischen DV-Netzwerk. Die im Trito (TC)- und Deutocerebrum (DC) entschlüsselten genetischen Interaktionen basieren überwiegend auf wechselseitiger Repression. Dementsprechend sorgen 1) Vnd und Ems durch gegenseitige Repression für eine frühe DV-Unterteilung des NE, und 2) wechselseitige Repression zwischen Nkx6 und Msh, als auch zwischen Ind und Msh für die Aufrechterhaltung der Grenze zwischen intermediärem und dorsalem NE. 3) Sowohl Ind als auch Msh sind in der Lage, die Expression von vnd zu inhibieren. Ferner konnte gezeigt werden, dass Vnd durch Repression von Msh als positiver Regulator von Nkx6 fungiert. Überdies beeinflusst Vnd die Expression von ind in segment-spezifischer Art und Weise: Vnd reprimiert ind-Expression im TC, sorgt jedoch für eine positive Regulation von ind im DC durch Repression von Msh. Auch der EGFR-Signalweg ist an der frühen DV-Regionalisierung des Gehirns beteiligt, indem er durch positive Regulation der msh-Repressoren Vnd, Ind und Nkx6 dazu beiträgt, dass die Expression von msh auf dorsales NE beschränkt bleibt. Ferner stellte sich heraus, dass das AP-Musterbildungsgen ems die Expression der DV-Gene kontrolliert und umgekehrt: Ems ist für die Aktivierung von Nkx6, ind und msh in TC und DC erforderlich ist, während Nkx6 und Ind zu einem späteren Zeitpunkt benötigt werden, um ems im intermediären DC gemeinsam zu reprimieren. Überdies konnte gezeigt werden, dass das Segmentpolaritätsgen en Aspekte der Expression von vnd, ind und msh in segment-spezifischer Art und Weise reguliert. En reprimiert ind und msh, hält jedoch vnd-Expression im DC aufrecht; im TC wird En benötigt, um die Expression von Msh herunter zu regulieren und somit die Aktivierung von ind dort zu ermöglichen.rnrnZusammengenommen zeigen diese Ergebnisse, dass AP Musterbildungsfaktoren in umfangreichen Maß die Expression der DV Gene im Gehirn (und VNS) kontrollieren. Ferner deuten diese Daten darauf hin, dass sich das „Konzept der ventralen Dominanz“, welches für die DV-Musterbildung im VNS postuliert wurde, nicht auf das genregulatorische Netzwerk im Gehirn übertragen lässt, da Interaktionen zwischen den beteiligten Faktoren hauptsächlich auf wechselseitiger (und nicht einseitiger) Repression basieren. Zudem scheint das Konzept der ventralen Dominanz auch für das VNS nicht uneingeschränkt zu gelten, da in dieser Arbeit u.a. gezeigt werden konnte, dass dorsal exprimiertes Msh in der Lage ist, intermediäres ind zu reprimieren. Interessanterweise ist gegenseitige Repression von Homöodomänen-Proteinen im sich entwickelnden Neuralrohr von Vertebraten weit verbreitet und darüberhinaus essenziell für den Aufbau diskreter DV-Vorläuferdomänen, und weist insofern eine große Ähnlichkeit zu den in dieser Arbeit beschriebenen DV-Musterbildungsvorgängen im frühembryonalen Fliegengehirn auf.rn