Browsing by Subject "birth defects"

Now showing 1 - 6 of 6
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    Extrahepatic anomalies in infants with biliary atresia: results of a large prospective North American multicenter study
    (Wiley, 2013-11) Schwarz, Kathleen B.; Haber, Barbara H.; Rosenthal, Philip; Mack, Cara L; Moore, Jeffrey; Bove, Kevin E.; Bezerra, Jorge A.; Karpen, Saul J.; Kerkar, Nanda; Shneider, Benjamin L.; Turmelle, Yumirle P.; Whitington, Peter F.; Molleston, Jean P.; Murray, Karen F.; Ng, Vicky L.; Romero, René; Wang, Kasper S.; Sokol, Ronald J.; Magee, John C.; Pediatrics, School of Medicine
    Background and aims The etiology of biliary atresia (BA) is unknown. Given that patterns of anomalies might provide etiopathogenetic clues, we utilized data from the North American Childhood Liver Disease Research and Education Network to analyze patterns of anomalies in infants with BA. Methods Two hundred eighty-nine infants who were enrolled into the prospective database prior to surgery at any of 15 centers participating were evaluated. Results Group 1 was non-syndromic, isolated BA (without major malformations) (n = 242, 84 %), Group 2 was BA and at least one malformation considered major as defined by the National Birth Defects Prevention Study but without laterality defects (n = 17, 6%). Group 3 was syndromic, with laterality defects (n = 30, 10%). In the population as a whole, anomalies (either major or minor) were most prevalent in the cardiovascular (16%) and gastrointestinal (14%) systems. Group 3 patients accounted for the majority of subjects with cardiac, gastrointestinal and splenic anomalies. Group 2 subjects also frequently displayed cardiovascular (71%) and gastrointestinal (24 %) anomalies; interestingly this group had genitourinary anomalies more frequently (47%) compared to Group 3 subjects (10%). Conclusions This study identified a group of BA (Group 2) that differed from the classical syndromic and non-syndromic groups and that was defined by multiple malformations without laterality defects. Careful phenotyping of the patterns of anomalies may be critical to the interpretation of both genetic and environmental risk factors associated with BA, allowing new insight into pathogenesis and/or outcome.
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    Marijuana and Opioid Use during Pregnancy: Using Zebrafish to Gain Understanding of Congenital Anomalies Caused by Drug Exposure during Development
    (MDPI, 2020-08-08) Sarmah, Swapnalee; Sales Cadena, Marilia Ribeiro; Cadena, Pabyton Gonçalves; Marrs, James A.; Biology, School of Science
    Marijuana and opioid addictions have increased alarmingly in recent decades, especially in the United States, posing threats to society. When the drug user is a pregnant mother, there is a serious risk to the developing baby. Congenital anomalies are associated with prenatal exposure to marijuana and opioids. Here, we summarize the current data on the prevalence of marijuana and opioid use among the people of the United States, particularly pregnant mothers. We also summarize the current zebrafish studies used to model and understand the effects of these drug exposures during development and to understand the behavioral changes after exposure. Zebrafish experiments recapitulate the drug effects seen in human addicts and the birth defects seen in human babies prenatally exposed to marijuana and opioids. Zebrafish show great potential as an easy and inexpensive model for screening compounds for their ability to mitigate the drug effects, which could lead to new therapeutics.
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    MOLECULAR AND CELLULAR MECHANISMS LEADING TO SIMILAR PHENOTYPES IN DOWN AND FETAL ALCOHOL SYNDROMES
    (Office of the Vice Chancellor for Research, 2012-04-13) Solzak, Jeffrey P.; Zhou, Feng C.; Roper, Randall J.
    Down syndrome (DS) and Fetal Alcohol Syndrome (FAS) are two leading causes of birth defects with phenotypes ranging from cognitive impairment to craniofacial abnormalities. While DS originates from the trisomy of human chromosome 21 and FAS from prenatal alcohol consumption, many of the defining characteristics for these two disorders are stunningly similar. A sur-vey of the literature revealed over 20 similar craniofacial and structural defi-cits in both human and mouse models of DS and FAS. We hypothesized that the similar phenotypes observed are caused by disruptions in common mo-lecular or cellular pathways during development. To test our hypothesis, we examined morphometric, genetic, and cellular phenotypes during develop-ment of our DS and FAS mouse models at embryonic days 9.5-10.5. Our preliminary evidence indicates that during early development, dysregulation of Dyrk1a and Rcan1, cardinal genes affecting craniofacial and neurological precursors of DS, are also dysregulated in embryonic FAS models. Further-more, Caspase 3 was also found to have similar expression in DS and FAS craniofacial neural crest derived tissues such as the first branchial arch (BA1) and regions of the brain. This may explain a developmental deficit by means of increased apoptosis. We are currently investigating the expression of pAkt, a protein shown to be affected in FAS models, in cells located in these same craniofacial and neurological regions in DS models. Recent re-search shows that Ttc3, a gene that is triplicated and shown to be overex-pressed in our DS mouse model, targets pAkt in the nucleus affecting im-portant transcription factors regulating cell cycle and cell survival. While Akt has been shown to play a role in neuronal development, we hypothesize that it also affects similar cellular properties in craniofacial precursors during de-velopment. By comparing common genotypes and phenotypes of DS and FAS we may provide common mechanisms to target for potential treatments of both disorders.
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    MOLECULAR AND CELLULAR MECHANISMS LEADING TO SIMILAR PHENOTYPES IN DOWN AND FETAL ALCOHOL SYNDROMES
    (Office of the Vice Chancellor for Research, 2011-04-08) Solzak, Jeffrey P.; Zhou, Feng; Roper, Randall J.
    Down syndrome (DS) and Fetal Alcohol Syndrome (FAS) are two leading causes of birth defects with phenotypes ranging from cognitive impairment to craniofacial abnormalities. These syndromes have an estimated occurrence of 1/750 and 1/1000 live births, respectively. While DS originates from the trisomy of human chromosome 21 and FAS from excess alcohol consumption, many of the defining characteristics for these two disorders are stunningly similar. Our research of the published literature has identified more than 20 similarities in DS and FAS phenotypes including precise craniofacial and neurological abnormalities. We hypothesize that the similar phenotypes in these two syndromes are caused by disruptions in common molecular and cellular pathways. To test our hypothesis we are examining morphometric, genetic, and cellular phenotypes during development of DS and FAS mouse models. Our preliminary evidence indicates that during early development, expression of Dyrk1a and Rcan1 (two genes found in three copies in individuals with DS) is dysregulated in the craniofacial and neurological precursors of both DS and FAS as compared to normal control embryos. Using immuocytochemistry, we are analyzing cellular properties of neurological development in DS embryos and comparing deficiencies found between trisomic and normal mice to those found in FAS embryos at similar stages. These results will further define molecular and cellular alterations leading to DS and FAS phenotypes and provide mechanisms to target for potential pharmacotherapy.
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    Nkx2.5 regulates Endothelin Converting Enzyme-1 during pharyngeal arch patterning
    (Wiley, 2017-03) Iklé, Jennifer M.; Tavares, Andre L. P.; King, Marisol; Ding, Ding; Colombo, Sophie; Firulli, Beth A.; Firulli, Firulli; Targoff, Kimara L.; Yelon, Deborah; Clouthier, David E.; Anatomy and Cell Biology, School of Medicine
    In gnathostomes, dorsoventral (D-V) patterning of neural crest cells (NCC) within the pharyngeal arches is crucial for the development of hinged jaws. One of the key signals that mediates this process is Endothelin-1 (EDN1). Loss of EDN1 binding to the Endothelin-A receptor (EDNRA) results in loss of EDNRA signaling and subsequent facial birth defects in humans, mice and zebrafish. A rate-limiting step in this crucial signaling pathway is the conversion of immature EDN1 into a mature active form by Endothelin converting enzyme-1 (ECE1). However, surprisingly little is known about how Ece1 transcription is induced or regulated. We show here that Nkx2.5 is required for proper craniofacial development in zebrafish and acts in part by upregulating ece1 expression. Disruption of nkx2.5 in zebrafish embryos results in defects in both ventral and dorsal pharyngeal arch-derived elements, with changes in ventral arch gene expression consistent with a disruption in Ednra signaling. ece1 mRNA rescues the nkx2.5 morphant phenotype, indicating that Nkx2.5 functions through modulating Ece1 expression or function. These studies illustrate a new function for Nkx2.5 in embryonic development and provide new avenues with which to pursue potential mechanisms underlying human facial disorders.
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    SHP-2 deletion in postmigratory neural crest cells results in impaired cardiac sympathetic innervation
    (National Academy of Sciences, 2014-04-08) Lajiness, Jacquelyn D.; Snider, Paige; Wang, Jian; Feng, Gen-Sheng; Krenz, Maike; Conway, Simon J.; Department of Pediatrics, School of Medicine
    Autonomic innervation is an essential component of cardiovascular regulation that is first established from the neural crest (NC) lineage in utero and continues developing postnatally. Although in vitro studies have indicated that SH2-containing protein tyrosine phosphatase 2 (SHP-2) is a signaling factor critical for regulating sympathetic neuron differentiation, this has yet to be shown in the complex in vivo environment of cardiac autonomic innervation. Targeting SHP-2 within postmigratory NC lineages resulted in a fully penetrant mouse model of diminished sympathetic cardiac innervation and concomitant bradycardia. Immunohistochemistry of the sympathetic nerve marker tyrosine hydroxylase revealed a progressive loss of adrenergic ganglionic neurons and reduction of cardiac sympathetic axon density in Shp2 cKOs. Molecularly, Shp2 cKOs exhibit lineage-specific suppression of activated phospo-ERK1/2 signaling but not of other downstream targets of SHP-2 such as pAKT. Genetic restoration of the phosphorylated-extracellular signal-regulated kinase (pERK) deficiency via lineage-specific expression of constitutively active MEK1 was sufficient to rescue the sympathetic innervation deficit and its physiological consequences. These data indicate that SHP-2 signaling specifically through pERK in postmigratory NC lineages is essential for development and maintenance of sympathetic cardiac innervation postnatally.