Elena Casey, see Elena Silva
Development of the neurons in the inner ear
The long-term goal of the research in the Coate laboratory will be to define the signaling mechanisms underlying neural development within sensory systems and how synaptic connections can be reestablished in cases of damage or disease. In the field of developmental neuroscience, we are now at an exciting time where we can take multi-faceted approaches to understanding (with excellent temporal and spatial resolution) the mechanisms by which precise cell types coordinate appropriate axon guidance decisions and synapse formation. In our research, we aim to understand the mechanisms by which spiral ganglion neurons (SGNs) make functional connections with mechanosensory hair cells in the mouse cochlea. We are currently addressing how secreted Semaphorins, which activate Neuropilin/Plexin co-receptors, control SGN axon guidance decisions in the cochlear sensory epithelium. We are also investigating how the transcription factor Pou3f4 controls the expression of axon guidance factors in the developing cochlea (such as ephrins and Eph receptors) and how those factors control cochlear innervation. The cochlea provides an excellent model for discovering how circuits assemble within a complex organ system, as it is composed of an array of cell types and structures precisely arranged to detect a range of sound frequencies.
The Donoghue Laboratory examines the development of the cerebral cortex, the largest and most complex portion of the mammalian forebrain. A battery of molecular, cellular, biochemical, and organismal approaches is used to examine the forces that shape the proper formation of the cortex. For example, current studies focus on how the proliferation of cells in immature cellular zones is controlled in development so that the mature cortex contains the appropriate number of cells. In addition, once cells have stopped dividing, we are interested in the regulatory programs that control their subsequent differentiation in more mature compartments. Together, we are interested in the coordination of cell genesis and cell differentiation in order to produce an integrated neural structure that has the proper cells present in the proper proportions. Mouse models (mutant, transgenic) are used for examining the function of particular genes in vivo and in vitro.
The goal of my research is to understand how glial cells regulate neuronal function in the mammalian central nervous system (CNS). We focus on oligodendrocytes, a type of glia, whose cellular processes engage with and enwrap CNS axons, and form the lipid-rich myelin membranes required for rapid, saltatory axonal conduction. Oligodendrocyte loss or dysfunction has profound impact on brain development, homoeostasis and aging, and has been implicated in many neurological disorders including certain leukodystrophies, multiple sclerosis (MS), cerebral palsy, Alzheimer’s disease, schizophrenia, and autism.
We are currently investigating the mechanisms by which oligodendrocytes interact and communicate with axons, and how their interactions might promote axonal integrity and survival. We are also investigating the mechanism of CNS regeneration, with a focus on how oligodendrocytes regenerate from endogenous neural progenitor cells to replace myelin during homeostatic turnover or after demyelination. We use primary oligodendrocyte/neuron co-cultures, transgenic mice, and models of experimental CNS injury and demyelination, combined with molecular biology and imaging tools to address these questions.
My research group has pioneered study the study of the neuorpeptide NAAG over the past two decades. We pursue the mechanisms through which NAAG chemically communicates information among cells. Our lab identified the receptors that this peptide activates and cloned two enzymes that mediate its inactivation. Currently, we are determining the role of endogenous NAAG at identified synapses, characterizing peptidases that hydrolyze NAAG in the nervous system, and developing novel compounds that inhibit these peptidases. These compounds decrease the rate of inactivation of the peptide and enhance its activity in the nervous system. My research group applies these compounds in animal models of important human disorders including chronic and inflammatory pain perception, schizophrenia, and excitotoxicity associated with traumatic brain injury. Our aim is to develop new therapies for these disorders.
The goal of the Casey lab is to understand the transcriptional regulation of a class of genes involved in the formation of the early vertebrate body plan. Patterning events such as the establishment of neural tissues require a series of signal transduction events that lead to the transcription of a set of genes. Few of the details of transcriptional regulation in vertebrate development have been deciphered. However, the ability to generate transgenic frogs has revolutionized the field, allowing rapid analysis of promoter function in a large number of embryos. This technique, along with embryology, traditional biochemical and molecular assays, and expression screens now enable us to define the factors required for regulation of genes involved in early vertebrate development.]