Epigenetic regulation of neuronal maturation : the effect of MeCP2 and MicroRNAs on the maturation of hippocampal neurons

Dendrites and the dendritic spines of neurons play key roles in the connectivity of the brain and have been recognized as the locus of long-term synaptic plasticity, which is correlated with learning and memory. The development of dendrites and spines in the mammalian central nervous system is a complex process that requires specific molecular events over a period of time. It has been shown that specific molecules are needed not only at the spines point of contact, but also at a distance, providing signals that initiate a cascade of events leading to synapse formation. The specific molecules that act to signal neuronal differentiation, dendritic morphology, and synaptogenesis are tightly regulated by genetic and epigenetic programs. It has been shown that the dendritic spine structure and distribution are altered in many diseases, including many forms of mental retardation (MR) such as Rett syndrome, and can also be potentiated by neuronal activities and an enriched environment. Because dendritic spine pathologies are found in many types of MR, it has been proposed that an inability to form normal spines leads to the cognitive and motor deficits that are characteristic of MR. Epigenetic mechanisms, including DNA methylation, chromatin remodeling, and the noncoding RNA-mediated process, have profound regulatory roles in mammalian gene expression. My dissertation research focused on two aspects of epigenetic mechanisms, Mecp2-DNA methylation pathway and noncoding microRNAs that regulate the development and maturation of dendrites and spines. It is well known that Rett Syndrome, a severe postnatal childhood neurological disorder is mostly caused by mutations in the MECP2 gene. My studies focused on the role of MeCP2-mediated epigenetic regulation in postnatal brain development in a Mecp2-deficient mouse model. I found that, while Mecp2 was not critical for the production of immature neurons in the dentate gyrus (DG) of the hippocampus, the newly generated neurons exhibited profound deficits in neuronal maturation, including delayed transition into a more mature stage, altered expression of presynaptic proteins, and reduced dendritic spine density. Furthermore, I found that cultured neurons and brains lacking Mecp2 exhibited altered expression of microRNAs. My studies demonstrate that one brain-enriched microRNA, miR-137, has a significant role in regulating neuronal maturation by translational regulation of Mind bomb1. Despite extensive efforts to understand the molecular regulation of dendrite and spine development, epigenetic and non-coding RNA pathways have only recently been considered. In this thesis, I will first summarize the literature on epigenetic mechanisms that regulate the development and maturation of dendrites and spines, and discuss some general methodologies as well as recent technological advances in biology and neurosciences. I will then present my own data to show how epigenetic alterations could result in the morphological and phenotypic abnormalities that are a fundamental characteristic MR, such as Rett syndrome

Recommended Expansion of Campus Historic District

Map of the recommended expansion of the University of Maine\u27s campus historic district. The proposed expansion was accepted by the National Register of Historic Places

The University of Maine Historic Preservation Master Plan

Historic Preservation Plan for the University of Maine. The plan represents the efforts of University of Maine personnel, including administrators, Facilities Management staff, faculty and students; and consulting architects, historians, and landscape architects, working closely with the CPC (and through representation on the CPC, the CBAC) and the MHPC. The University’s Board of Visitors periodically reviewed the work of the planning team and offered enthusiastic support. The goals of the Historic Preservation Master Plan are to:• identify and document historic resources of the core campus of the University of Maine;• identify more recent buildings and landscapes of the University of Maine that have acquired or are expected to acquire significance in the future;• determine and document existing conditions of these resources;• recommend appropriate preservation treatmentsand uses for these resources;• publicize and protect these resources through designation under institutional, local, state and federal historic preservation processes;• put in place University policies and procedures that will assure adequate protection, maintenance, and appropriate use of these resources;• use University resources to educate the University community about the importance and value of campus historic resources;• protect the historic resources of the University in order to maintain strong ties between the institution and its alumni family; and• provide campus planners with specific and practical information to assist them with the day-to-day management of the physical plant and with long-range development decisions

3′-O-Acetyl-2′-de­oxy­uridine

In the two independent but very similar mol­ecules of the title compound, C11H14N2O6, both nucleobase fragments are nearly planar (both within 0.01 Å) while the furan­ose rings exhibit 2 E-endo envelope conformations. In the crystal, the two 3′-O-acetyl-2′-de­oxy­uridine mol­ecules form a pseudosymmetric dimer of two bases connected via two nearly identical resonance-assisted N—H⋯O hydrogen bonds. The resulting pair is further connected with neighboring pairs via two similar O—H⋯O bonds involving the only hydroxyl group of the 2′-de­oxy­furan­ose fragment and the remaining carbonyl oxygen of the nucleobase. These inter­actions result in the formation of an infinite ‘double band’ along the b axis that can be considered as a self-assembled analogue of a polynucleotide mol­ecule with non-canonical Watson–Crick base pairs. The infinite chains of 3′-O-acetyl-2′-de­oxy­uridine pairs are additionally held together by C—H⋯O inter­actions involving C atoms of the uracyl base and O atoms of carbonyl groups. Only weak C—H⋯O contacts exist between neighboring chains

Lipids Regulate Lck Protein Activity through Their Interactions with the Lck Src Homology 2 Domain.

Lymphocyte-specific protein-tyrosine kinase (Lck) plays an essential role in T cell receptor (TCR) signaling and T cell development, but its activation mechanism is not fully understood. To explore the possibility that plasma membrane (PM) lipids control TCR signaling activities of Lck, we measured the membrane binding properties of its regulatory Src homology 2 (SH2) and Src homology 3 domains. The Lck SH2 domain binds anionic PM lipids with high affinity but with low specificity. Electrostatic potential calculation, NMR analysis, and mutational studies identified the lipid-binding site of the Lck SH2 domain that includes surface-exposed basic, aromatic, and hydrophobic residues but not the phospho-Tyr binding pocket. Mutation of lipid binding residues greatly reduced the interaction of Lck with the chain in the activated TCR signaling complex and its overall TCR signaling activities. These results suggest that PM lipids, including phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate, modulate interaction of Lck with its binding partners in the TCR signaling complex and its TCR signaling activities in a spatiotemporally specific manner via its SH2 domain.1175Ysciescopu

MECP2 genomic structure and function: insights from ENCODE

MECP2, a relatively small gene located in the human X chromosome, was initially described with three exons transcribing RNA from which the protein MeCP2 was translated. It is now known to have four exons from which two isoforms are translated; however, there is also evidence of additional functional genomic structures within MECP2, including exons potentially transcribing non-coding RNAs. Accompanying the recognition of a higher level of intricacy within MECP2 has been a recent surge of knowledge about the structure and function of human genes more generally, to the extent that the definition of a gene is being revisited. It is timely now to review the published and novel functional elements within MECP2, which is proving to have a complexity far greater than was previously thought

MIR137 is the key gene mediator of the syndromic obesity phenotype of patients with 1p21.3 microdeletions.

BACKGROUND: Deletions in the long arm of chromosome 1 have been described in patients with a phenotype consisting primarily of obesity, intellectual disability and autism-spectrum disorder. The minimal region of overlap comprises two genes: DPYD and MIR137. CASE PRESENTATION: We describe a 10-year-old boy with syndromic obesity who carries a novel 1p21.3 deletion overlapping the critical region with the MIR137 gene only. CONCLUSIONS: This study suggests that MIR137 is the mediator of the obesity phenotype of patients carrying 1p21.3 microdeletions

Fragile X Mental Retardation Protein Regulates Proliferation and Differentiation of Adult Neural Stem/Progenitor Cells

Fragile X syndrome (FXS), the most common form of inherited mental retardation, is caused by the loss of functional fragile X mental retardation protein (FMRP). FMRP is an RNA–binding protein that can regulate the translation of specific mRNAs. Adult neurogenesis, a process considered important for neuroplasticity and memory, is regulated at multiple molecular levels. In this study, we investigated whether Fmrp deficiency affects adult neurogenesis. We show that in a mouse model of fragile X syndrome, adult neurogenesis is indeed altered. The loss of Fmrp increases the proliferation and alters the fate specification of adult neural progenitor/stem cells (aNPCs). We demonstrate that Fmrp regulates the protein expression of several components critical for aNPC function, including CDK4 and GSK3β. Dysregulation of GSK3β led to reduced Wnt signaling pathway activity, which altered the expression of neurogenin1 and the fate specification of aNPCs. These data unveil a novel regulatory role for Fmrp and translational regulation in adult neurogenesis