Gerald Schwarting PhD
|Institution||University of Massachusetts Medical School|
|Department||Cell and Developmental Biology|
|Address||University of Massachusetts Medical School|
55 Lake Avenue North
Worcester MA 01655
|Institution||UMMS - Graduate School of Biomedical Sciences|
|Institution||UMMS - Graduate School of Biomedical Sciences|
Gary Schwarting received his B. A. from the University of Connecticut in 1969, and his Ph. D. from the University of Munich, Germany in 1974. He was an NIH post-doctoral fellow at Albert Einstein College of Medicine in the Department of Microbiology and Immunology from 1975-77. He joined the Shriver Center in 1977 and has been on the University of Massachusetts Medical School faculty since 2000.
Axon Guidance in the Developing Olfactory System
We are investigating the factors that regulate the guidance of connections between sensory neurons in the olfactory epithelium (OE) and their targets (glomeruli) in the olfactory bulb (OB). We have previously demonstrated that neuropilin-1+ (Nnn-1) axons grow exclusively to targets in the medial and lateral OB but not the ventral or dorsal OB. Recently we have recently shown demonstrated that a glycan, Lactosamine also plays a role in axon guidance. The glycosyltransferase b3GnT1 is expressed in neurons in the olfactory epithelium and is the key determinant of Lactosamine expression. It is expressed on the cilia, cell soma and axons on a subset of mature sensory neurons and on targets in the ventral OB, a region where Npn-1 axons are excluded by the repulsive guidance cue Sema3A. In mice lacking b3GnT1, there is a profound axon guidance defect. Axons that normally target the posterior OB are misdirected toward the anterior OB (Figure 1). Interestingly, it has recently been shown that regulation of cAMP and other signaling molecules play a role in axon guidance and are currently investigating the possibility that N-glycosylation by b3GnT1 may play an important role in the expression of key signaling molecules in the OE and OB. These studies suggest that axon guidance is governed by restricted expression of permissive and non-permissive cues that successively restrict subsets of axons into more refined target regions of the developing OB. Our objective is to identify additional guidance mechanisms that further subdivide these targeting compartments into smaller and smaller segments of the OB until precise convergence of axons onto a small number of glomeruli is achieved.
Cell Migration in the Developing Olfactory System
In collaboration with Dr Stuart Tobet and Colorado State University, we are investigating factors that regulate the migration of gonadotropin-releasing hormone (GnRH) neurons. In embryonic mice about 1500 GnRH neurons migrate from the vomeronasal organ (VNO) in the nose across the cribriform plate to the forebrain. The migration of these neurons is essential for reproductive competence in mature mammals, including humans. We have previously shown that GnRH neurons use axons as their guides and that these neurons express a variety of receptors that govern their migration. These axon guides express the netrin-1 receptor deleted in colon cancer (DCC) and turn toward a source of netrin-1 in the ventral forebrain. GnRH neurons normally follow those guides to the ventral forebrain, but in DCC and netrin-1 mutant mice, axons fail to turn ventrally and most GnRH neurons migrate into the cerebral cortex rather than the hypothalamus (see Figure 2). GnRH neurons also express CXCR4, the receptor for stromal cell derived factor 1 (SDF-1), which is expressed in a gradient in the nasal mesenchyme. In CXCR4 null mice, most GnRH neurons fail to migrate out of the nasal mesenchyme during embryonic development. In individuals with Kallmann’s syndrome, GnRH neurons fail to migrate properly but only in a small percentage of cases has a genetic link been identified. Our objectives are to identify additional factors that regulate GnRH neuron migration and to better understand the causes of Kallmann’s and similar syndromes.
Glycoconjugates in Cell-Cell Interactions
Mechanisms of GNRH Neuron Migration During Development
Figure 1. The M72 odorant receptor is expressed on axons that project to a dorsal target (A) and to medial glomerulus (B). In b3GnT1 null mice, the dorsal M72 glomerulus is shifted to the rostral-medial OB (C). In wild-type mice each glomerulus contains axons expressing only one OR, but in null mice glomeruli express more than one OR (D).
Figure 2. GnRH neurons migrate from the vomeronasal organ (VNO) across the cribriform plate (CP) into the forebrain. They turn ventrally following DCC+ axons toward the median eminence (me) and arcuate nucleus (arc). Factors that regulate migration at various stages include netrin-1, stromal cell derived factor-1 (SDF-1) and their respective receptors CXCR4 and DCC.
Potential Rotation Projects
Project #1: The soluble chemoattractant/repellent netrin-1 is expressed in the ventricular zone of the developing olfactory bulb and by neurons in the olfactory epithelium in the early mouse embryo at a time when the olfactory system is being patterned. Two netrin-1 receptors, DCC and Unc5h3 are expressed by different cell types in the developing olfactory system. The trajectories of axon subsets and positions of neuronal populations will be examined in Netrin-1, DCC, and Unc5h3 mutant mice from embryonic day 12 to birth, the time frame in which patterning of the olfactory system takes place. Explant culture experiments will also be carried out in conjunction with the use of function-blocking antibodies to determine the role of these proteins in olfactory development.
Project #2: In vitro slice preparations from developing mammalian embryos have significantly advanced the understanding of migratory behavior of cells in the cerebellum, cerebral cortex, and most recently in our studies of the hypothalamus. Our in vitro organotypic slice procedures allow us to directly examine the movements of cells across the developing rodent nasal septum and through the brain. Green Fluorescent Protein (GFP) allows the targeted expression of a fluorescent marker that can be visualized in live cells. A mouse line that expresses GFP specifically in LHRH cells is now on hand in my lab and will allow us to follow the migration of identified LHRH cells in vivo and in vitro as they move along olfactory and brain pathways. Techniques include the preparation of slices of entire embryonic heads, in which functional migratory connections can be maintained between the nasal cavity and basal forebrain in vitro. Immunofluorescence, confocal and light microscopic techniques allow us to follow live migrating LHRH cells into the forebrain and will allow us to test molecules that are important for regulating cell migration.
A postdoctoral position is available to study in this laboratory. Contact Dr. Schwarting for additional details.
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