GPR56/ADGRG1 regulates development and maintenance of peripheral myelin

Myelin is a multilamellar sheath generated by specialized glia called Schwann cells (SCs) in the peripheral nervous system (PNS), which serves to protect and insulate axons for rapid neuronal signaling. In zebrafish and rodent models, we identify GPR56/ADGRG1 as a conserved regulator of PNS development and health. We demonstrate that, during SC development, GPR56-dependent RhoA signaling promotes timely radial sorting of axons. In the mature PNS, GPR56 is localized to distinct SC cytoplasmic domains, is required to establish proper myelin thickness, and facilitates organization of the myelin sheath. Furthermore, we define plectin-a scaffolding protein previously linked to SC domain organization, myelin maintenance, and a series of disorders termed "plectinopathies"-as a novel interacting partner of GPR56. Finally, we show that Gpr56 mutants develop progressive neuropathy-like symptoms, suggesting an underlying mechanism for peripheral defects in some human patients with GPR56 mutations. In sum, we define Gpr56 as a new regulator in the development and maintenance of peripheral myelin

Novel Roles of the Type I bHLH proteins Daughterless/Tcf4 in Postmitotic Neurons of the Central Nervous System

Neurogenesis, the production of neuronal and glial lineages from undifferentiated precursor cells, is a critical step for embryonic neurodevelopment. Later in development, these cells become postmitotic, attaining cellular senescence and cease to divide. Proneural proteins of Class I/II Basic helix-loop-helix (bHLH) proteins are a large family of evolutionarily conserved transcription factors that have well-established roles in neurogenesis and neural differentiation across multiple species. Historically, our understanding of the function of class I/II transcription factors has largely focused on their function as regulators of neurogenesis, however their role in post-mitotic neurons remain unclear. The major objective of this work was to explore the role of bHLH transcription factor Daughterless (Da, Tcf4 in mammals) in postmitotic, differentiated motor neurons. The first set of studies, Chapter II, demonstrates that Da is expressed in postmitotic neurons in Drosophila melanogaster and is required to restrict synaptic growth and axonal arborization at the Drosophila neuromuscular junction (NMJ). We used bioinformatic tools to identify candidate genes whose transcription is regulated by Da and have identified and validated that cell-adhesion molecule neurexin is required for Da-mediated restriction of synaptic growth. In the second set of studies, Chapter III, we show that Tcf4 is also expressed in mouse brain postmitotic neurons, and mouse Tcf4 also functions to restrict synaptogenesis in mouse neurons. We outline a novel role for Class I proteins Da/Tcf4 outside of their established roles in neurogenesis, and conclude a novel function of class I bHLH proteins in neural function. In all, our studies are important to human health because mutations in Tcf4 have been linked to autism spectrum disorders and schizophrenia. Our integrative approach will provide a paradigm for how class I bHLH proteins can control different target genes in postmitotic neurons and are critical building models to better understand the etiology of these diseases and design possible therapeutic.Ph.D., Biological Sciences -- Drexel University, 201

MAP kinase phosphorylation is dispensable for cell division, but required for cell growth in Drosophila

Proper activation of the Ras/MAPK pathway is broadly required during development, and in many cases, signal transduction downstream of the receptor is linear. Thus, different mechanisms exist to properly regulate the large number of specific developmental outputs that are required by the activation of this pathway. Previously, we have reported a regulated cytoplasmic sequestration of phosphorylated MAPK (pMAPK) in developing Drosophila compound eyes and wings “called MAPK Cytoplasmic Hold”. In the developing wing, we have shown that cytoplasmic hold promotes the differentiation of wing vein tissue, while pMAPK nuclear translocation regulates growth and division. We had also suggested that the Ras pathway signals for inducing cell growth and cell division split upstream of the nuclear translocation of MAPK itself. Here, we further refine the role of MAPK in Drosophila. We report evidence that suggests, for the first time, that the phosphorylation of MAPK is itself another step in the regulation of cell growth and division in both Drosophila wing and eye cells. We show that inhibition of MAPK phosphorylation, or pMAPK nuclear translocation, is sufficient to block cell growth, but not cell division. These data suggest that non-phosphorylated MAPK is sufficient to induce cell division, but not cell growth, once inside the nucleus of the cell

A high-latitude Gondwanan lagerstätte: The Permian permineralised peat biota of the Prince Charles Mountains, Antarctica

The Toploje Member chert is a Roadian to Wordian autochthonous–parautochthonous silicified peat preserved within the Lambert Graben, East Antarctica. It preserves a remarkable sample of terrestrial life from highlatitude central Gondwana prior to the Capitanian mass extinction event from both mega- and microfossil evidence that includes cryptic components rarely seen in other fossil assemblages. The peat layer is dominated by glossopterid and cordaitalean gymnosperms and containsmoderately common herbaceous lycophytes, together with a broad array of dispersed organs of ferns and other gymnosperms. Rare arthropod–plant and fungal–plant interactions are preserved in detail, together with a plethora of fungal morphotypes, Peronosporomycetes, arthropod remains and a diverse coprolite assemblage. Comparisons to other Palaeozoic ecosystems show that the macro flora is of low diversity. The fungal and invertebrate–plant associations demonstrate that a multitude of ecological interactions were well developed by the Middle Permian in high-latitude forest mires that contributed to the dominant coal deposits of the Southern Hemisphere. Quantitative analysis of the constituents of the silicified peat and of macerals within adjacent coal seams reveals that whilst silicified peats provide an unparalleled sample of the organisms forming Permian coals, they do not necessarily reflect the volumetric proportions of constituents within the derived coal. The Toploje Member chert Lagerstätte provides a snapshot of a rapidly entombed mire climax ecosystem in the closing stages of the Palaeozoic, but prior to the onset of the protracted crisis that engulfed and overthrew these ecosystems at the close of the Permian.Reconstructing the lost forests of Antarctica: the palaeoecology, anatomy and phylogeny of the iconic Glossopteris floraExceptional permineralized biotas - windows into the evolution and functional diversity of terrestrial ecosystems through tim