Browsing by Subject "Embryology"
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Item Role of Neuroligin in Synapse Formation and Autism(2006-08-11) Chubykin, Alexander Anatoly; Südhof, Thomas C.Neuroligins mediate synaptogenesis through formation of a trans-synaptic complex with presynaptic neurexins. Interaction of neuroligin 1 with neurexins is regulated by alternative splicing of both neuroligin 1 (at splice site B) and of neurexins (at splice site #4). Full-length neuroligin 1 that binds only beta -neurexin more potently promotes synapse formation in hippocampal neurons, whereas neuroligin 1 lacking splice site B, which binds both alpha - and beta -neurexins, is more efficient at synapse expansion. Mutations in two surface loops of neuroligin 1 abolished neuroligin binding to neurexin 1beta and blocked synapse formation. Neuroligin mutation found in autism spectrum disorders impairs cell-surface transport but does not completely abolish synaptogenic activity. In hippocampal neurons, overexpressed neuroligin 1 enhances excitatory but not inhibitory synaptic responses, and increases the ratio of NMDA to AMPA receptor-mediated synaptic currents. In contrast, genetic deletion of neuroligin 1 in mice decreases NMDA receptor-mediated synaptic currents and the NMDA/AMPA receptor ratio. Contrary to neuroligin 1, neuroligin 2 potentiates inhibitory but not excitatory synaptic responses. The synaptic actions of neuroligin 1 are suppressed by chronic blockade of NMDA receptors or of CaM-kinase II. Neuroligin 1 with an autistic-spectrum syndrome mutation decreases excitatory synaptic responses, consistent with a role for endogenous neuroligin 1 in synapse development. Taken together, our data suggest that neuroligin-neurexin interaction regulated by their alternative splicing promotes formation of specific synapses; synaptogenic function of neuroligin is regulated by NMDA receptor and Cam-kinase II activation, suggesting a critical role for neuroligins in synaptic plasticity and modulation of neural circuits.Item Transcriptional and Translational Regulation of Heart Development in Mammals(2008-09-18) Ransom, Joshua Fuller; Srivastava, DeepakThe heart is the first organ to form in the embryo to support the growing need for oxygen and nutrients. To form correctly, this vital organ requires a high degree of regulation. Thus far, almost every known form of regulation that the mammalian cell has evolved is utilized in the proper development of the heart. Because the heart is so highly regulated, there are many steps at which a wrong turn can be made, leading to congenital cardiovascular malformations, which occur in one percent of all births and are the leading non-infectious cause of death in the first year of life. The majority of genes known to be involved in cardiogenesis in mammals are grouped at nodes which control many simultaneous aspects of differentiation, morphology, and heart size. This thesis work will discuss three separate lines of inquiry into cardiogenic nodes in mammalian heart development. The first deals with post-translational regulation of the Myocardin-dependent transcriptional node. The second story delves into the role of the Notch signaling pathway in human disease and how Notch regulates Myocardin and its downstream target gene, microRNA-1. The final account looks into regulation of protein translation through microRNAs in the heart with emphasis on microRNA-1-2.Item Transcriptional Regulation of Neural Crest-Derived Pharyngeal Arch Artery Development(2004-12-15) Ivey, Kathryn Nicole; Mendelson, Carole R.The heart is the first organ to form and is required for growth and development of mammalian embryos. As the heart matures, formation of the outflow tract is vital to establish appropriate connections with the vasculature. This process requires contribution from specialized neural crest cells, which originate in the neural folds and migrate to give rise to specific segments of the great vessels as well as particular facial structures. Many syndromic birth defects in humans affecting the heart and face arise as a result of inappropriate development of neural crest cells and can be modeled in animals through ablation of premigratory neural crest cells or targeted deletion of genes required for their proliferation, migration or survival. However, the transcription factors and signaling molecules that specify unique subsets of neural crest cells are still being detailed. This thesis represents efforts to understand those particulars. Endothelin-1 (Et-1), a small signaling peptide, is important for development of neural crest-derived structures and targeted deletion of the gene encoding Et-1 or its receptor, Endothelin-A (EtA), results in craniofacial and outflow tract anomalies along with downregulation of particular neural crest-derived pharyngeal arch mesenchyme markers. Mice deficient for both Gaq and Ga 11 are phenotypically similar to EtA or Et-1-null mice. My analysis of expression patterns of Et-1 dependent and independent transcription factors in Gaq /G a11-deficient embryos revealed that expression of genes encoding Et-1 dependent transcription factors was specifically downregulated in the pharyngeal arches of Gaq /G a11-deficient mice indicating that Gaq and Ga11 proteins serve as intracellular mediators of Et-1 signaling in the pharyngeal arch mesenchyme. Et-1 is also important for development of the neural crest-derived fetal vessel, the ductus arteriosus, which bridges the pulmonary and systemic circulations during gestation and must close at birth for extrauterine survival. The ductus arteriosus is composed of highly differentiated, contractile smooth muscle. I found that Et-1 is expressed specifically in the smooth muscle of the ductus arteriosus during development along with Hif2a and Ap2ᠡnd that, through epistatic relationships and negative feedback regulation, these three factors cooperatively regulate development of the specialized, neural crest-derived smooth muscle of this vessel.