Biomedical subjects

Gerald A Schwarting

Publications and source records attributed to Gerald A Schwarting.

9 recordsLinked to original sources

PubMed2007

Patterning the developing and regenerating olfactory system.

The olfactory system is a remarkable model for investigating the factors that influence the guidance of sensory axon populations to specific targets in the CNS. Since the initial discovery of the vast odorant receptor (ORs) gene family in rodents and the subsequent finding that these molecules directly influence targeting, several additional olfactory axon guidance cues have been identified. Two of these, ephrins and semaphorins, have well-established functions in patterning axon connections in other systems. In addition, lactosamine-containing glycans are also required for proper targeting and maintenance of olfactory axons, and may also function in other sensory regions. It is now apparent that these and likely other additional molecules are required along with ORs to orchestrate the complex pattern of convergence and divergence that is unique to the olfactory system.

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PubMed2006

Stromal cell-derived factor-1 (chemokine C-X-C motif ligand 12) and chemokine C-X-C motif receptor 4 are required for migration of gonadotropin-releasing hormone neurons to the forebrain.

Gonadotropin-releasing hormone (GnRH) neurons migrate from the vomeronasal organ (VNO) in the nasal compartment to the basal forebrain in mice, beginning on embryonic day 11 (E11). These neurons use vomeronasal axons as guides to migrate through the nasal mesenchyme. Most GnRH neurons then migrate along the caudal branch of the vomeronasal nerve to reach the hypothalamus. We show here that stromal cell-derived factor-1 [SDF-1, also known as chemokine C-X-C motif ligand 12 (CXCL12)] is expressed in the embryonic nasal mesenchyme from as early as E10 in an increasing rostral to caudal gradient that is most intense at the border of the nasal mesenchyme and the telencephalon. Chemokine C-X-C motif receptor 4 (CXCR4), the receptor for SDF-1, is expressed by neurons in the olfactory epithelium and VNO. Cells derived from these sensory epithelia, including migrating GnRH neurons and ensheathing glial precursors of the migrating mass (MM), also express CXCR4, suggesting that they may use SDF-1 as a chemokine. In support of this, most GnRH neurons of CXCR4-/- mice fail to exit the VNO at E13, and comparatively few GnRH neurons reach the forebrain. There is also a significant decrease in the total number of GnRH neurons in CXCR4-/- mice and an increase in cell death within the VNO relative to controls. The MM is smaller in CXCR4-/- mice, suggesting that some MM cells also require SDF-1/CXCR4 function for migration and survival.

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PubMed2006

Lactosamine modulates the rate of migration of GnRH neurons during mouse development.

Gonadotropin-releasing hormone (GnRH) neurons are derived from progenitor cells in the olfactory placodes and migrate from the vomeronasal organ (VNO) across the cribriform plate into the forebrain. At embryonic day (E)12 in the mouse most of these neurons are still in the nasal compartment but by E15 most GnRH neurons have migrated into the forebrain. Glycoconjugates with carbohydrate chains containing terminal lactosamine are expressed by neurons in the main olfactory epithelium and in the VNO. One of the key enzymes required to regulate the synthesis and expression of lactosamine, beta1,3-N-acetylglucosaminyltransferase-1 (beta3GnT1), is strongly expressed by neurons in the olfactory epithelium and VNO, and on neurons migrating out of the VNO along the GnRH migratory pathway. Immunocytochemical analysis of lactosamine and GnRH in embryonic mice reveals that the percentage of lactosamine+-GnRH+ double-labeled neurons decreases from > 80% at E13, when migration is near its peak, to approximately 30% at E18.5, when most neurons have stopped migrating. In beta3GnT1-/- mice, there is a partial loss of lactosamine expression on GnRH neurons. Additionally, a greater number of GnRH neurons were retained in the nasal compartment of null mice at E15 while fewer GnRH neurons were detected later in embryonic development in the ventral forebrain. These results suggest that the loss of lactosamine on a subset of GnRH neurons impeded the rate of migration from the nose to the brain.

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PubMed2005

Minireview: recent progress in gonadotropin-releasing hormone neuronal migration.

Neurons that synthesize GnRH are critical brain regulators of the reproductive axis, yet they originate outside the brain and must migrate over long distances and varied environments to get to their appropriate positions during development. Many studies, past and present, are providing clues for the types of molecules encountered and movements expected along the migratory route. Recent studies provide real-time views of the behavior of GnRH neurons in the context of in vitro preparations that model those in vivo. Live images provide direct evidence of the changing behavior of GnRH neurons in their different environments, showing that GnRH neurons move with greater frequency and with more alterations in direction after they enter the brain. The heterogeneity of molecular phenotypes for GnRH neurons likely ensures that multiple external factors will be found that regulate the migration of different portions of the GnRH neuronal population at different steps along the route. Molecules distributed in gradients both in the peripheral olfactory system and basal forebrain may be particularly influential in directing the appropriate movement of GnRH neurons along their arduous migration. Molecules that mediate the adhesion of GnRH neurons to changing surfaces may also play critical roles. It is likely that the multiple external factors converge on selective signal transduction pathways to engage the mechanical mechanisms needed to modulate GnRH neuronal movement and ultimately migration.

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PubMed2005

Beta1,3-N-acetylglucosaminyltransferase 1 glycosylation is required for axon pathfinding by olfactory sensory neurons.

During embryonic development, axons from sensory neurons in the olfactory epithelium (OE) extend into the olfactory bulb (OB) where they synapse with projection neurons and form glomerular structures. To determine whether glycans play a role in these processes, we analyzed mice deficient for the glycosyltransferase beta1,3-N-acetylglucosaminyltransferase 1 (beta3GnT1), a key enzyme in lactosamine glycan synthesis. Terminal lactosamine expression, as shown by immunoreactivity with the monoclonal antibody 1B2, is dramatically reduced in the neonatal null OE. Postnatal beta3GnT1-/- mice exhibit severely disorganized OB innervation and defective glomerular formation. Beginning in embryonic development, specific subsets of odorant receptor-expressing neurons are progressively lost from the OE of null mice, which exhibit a postnatal smell perception deficit. Axon guidance errors and increased neuronal cell death result in an absence of P2, I7, and M72 glomeruli, indicating a reduction in the repertoire of odorant receptor-specific glomeruli. By approximately 2 weeks of age, lactosamine is unexpectedly reexpressed in sensory neurons of null mice through a secondary pathway, which is accompanied by the regrowth of axons into the OB glomerular layer and the return of smell perception. Thus, both neonatal OE degeneration and the postnatal regeneration are lactosamine dependent. Lactosamine expression in beta3GnT1-/- mice is also reduced in pheromone-receptive vomeronasal neurons and dorsal root ganglion cells, suggesting that beta3GnT1 may perform a conserved function in multiple sensory systems. These results reveal an essential role for lactosamine in sensory axon pathfinding and in the formation of OB synaptic connections.

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PubMed2004

Live view of gonadotropin-releasing hormone containing neuron migration.

Neurons that synthesize GnRH control the reproductive axis and migrate over long distances and through different environments during development. Prior studies provided strong clues for the types of molecules encountered and movements expected along the migratory route. However, our studies provide the first real-time views of the behavior of GnRH neurons in the context of an in vitro preparation that maintains conditions comparable to those in vivo. The live views provide direct evidence of the changing behavior of GnRH neurons in their different environments, showing that GnRH neurons move with greater frequency and with more changes in direction after they enter the brain. Perturbations of guiding fibers distal to moving GnRH neurons in the nasal compartment influenced movement without detectable changes in the fibers in the immediate vicinity of moving GnRH neurons. This suggests that the use of fibers by GnRH neurons for guidance may entail selective signaling in addition to mechanical guidance. These studies establish a model to evaluate the influences of specific molecules that are important for their migration.

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PubMed2004

Netrin 1-mediated chemoattraction regulates the migratory pathway of LHRH neurons.

Luteinizing hormone-releasing hormone (LHRH) neurons migrate from the vomeronasal organ (VNO) to the forebrain in all mammals studied. In mice, the direction of LHRH neuron migration is dependent upon axons that originate in the VNO, but bypass the olfactory bulb and project caudally into the basal forebrain. Thus, factors that guide this unique subset of vomeronasal axons that comprise the caudal vomeronasal nerve (cVNN) are candidates for regulating the migration of LHRH neurons. We previously showed that deleted in colorectal cancer (DCC) is expressed by neurons that migrate out of the VNO during development [Schwarting et al. (2001) J. Neurosci., 21, 911-919]. We examined LHRH neuron migration in Dcc-/- mice and found that trajectories of the cVNN and positions of LHRH neurons are abnormal. Here we extend these studies to show that cVNN trajectories and LHRH cell migration in netrin 1 (Ntn1) mutant mice are also abnormal. Substantially reduced numbers of LHRH neurons are found in the basal forebrain and many LHRH neurons migrate into the cerebral cortex of Ntn1 knockout mice. In contrast, migration of LHRH cells is normal in Unc5h3rcm mutant mice. These results are consistent with the idea that the chemoattraction of DCC+ vomeronasal axons by a gradient of netrin 1 protein in the ventral forebrain guides the cVNN, which, in turn, determines the direction of LHRH neuron migration in the forebrain. Loss of function through a genetic deletion in either Dcc or Ntn1 results in the migration of many LHRH neurons to inappropriate destinations.

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PubMed2004

Semaphorin 3A-mediated axon guidance regulates convergence and targeting of P2 odorant receptor axons.

Semaphorins are known to play an important role in axon guidance of vertebrate olfactory sensory neurons to their targets in specific glomeruli of the olfactory bulb (OB). However, it is not clear how semaphorin-mediated guidance contributes to a systematic hierarchy of cues that govern the organization of this system. Because of the putative role that odorant receptor molecules such as P2 could play in establishing appropriate glomerular destinations for growing olfactory axons, we have also determined the spatial organization of P2 glomeruli in semaphorin 3A (Sema3A) mutant mice. First, in the postnatal OB of control and Sema3A(-/-) mice, we analysed the trajectories of olfactory axons that express the Sema3A receptor, neuropilin-1 (npn-1) and the positions of npn-1(+) glomeruli. Sema3A at the ventral OB midline guides npn-1(+) axons to targets in the lateral and medial OB. Absence of Sema3A permits many npn-1 axons to terminate aberrantly in the rostral and ventral OB. Second, in Sema3A(-/-) mice, many P2 axons are abnormally distributed throughout the ventral OB nerve layer and converge in atypical locations compared with littermate controls where P2 axons converge on stereotypically located lateral and medial glomeruli. In addition to their radically altered spatial distribution, P2 glomeruli in Sema3A(-/-) mice are significantly smaller and more numerous than in heterozygote littermates. These data show that Sema3A is an important repulsive olfactory guidance cue that establishes restricted npn-1(+) subcompartments in the olfactory bulb. Furthermore, Sema3A plays a key role in the convergence of axons expressing the odorant receptor P2 onto their appropriate targets.

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PubMed2003

Overexpression of glutamic acid decarboxylase-67 (GAD-67) in gonadotropin-releasing hormone neurons disrupts migratory fate and female reproductive function in mice.

gamma-Aminobutyric acid (GABA) inhibits the embryonic migration of GnRH neurons and regulates hypothalamic GnRH release. A subset of GnRH neurons expresses GABA along their migratory route in the nasal compartment before entering the brain, suggesting that GABA produced by GnRH neurons may help regulate the migratory process. To examine this hypothesis and the possibility that persistence of GABA production by GnRH neurons may affect subsequent reproductive function, we generated transgenic mice in which the expression of glutamic acid decarboxylase-67 (GAD-67), a key enzyme in GABA synthesis, is targeted to GnRH neurons under the control of the GnRH gene promoter. On embryonic d 15, when GnRH neurons are still migrating, the transgenic animals had more GnRH neurons in aberrant locations in the cerebral cortex and fewer neurons reaching the hypothalamic-preoptic region, whereas migration into the brain was not affected. Hypothalamic GnRH content in mutant mice was low during the first week of postnatal life, increasing to normal values during infantile development (second week after birth) in the presence of increased pulsatile GnRH release. Consistent with these changes, serum LH and FSH levels were also elevated. Gonadotropin release returned to normal values by the time steroid negative feedback became established (fourth week of life). Ovariectomy at this time demonstrated an enhanced gonadotropin response in transgenic animals. Although the onset of puberty, as assessed by the age at vaginal opening and first ovulation, was not affected in the mutant mice, estrous cyclicity and adult reproductive capacity were disrupted. Mutant mice had reduced litter sizes, increased time intervals between deliveries of litters, and a shorter reproductive life span. Thus, GABA produced within GnRH neurons does not delay GnRH neuronal migration, but instead serves as a developmental cue that increases the positional diversity of these neurons within the basal forebrain. In addition, the results suggest that the timely termination of GABA production within the GnRH neuronal network is a prerequisite for normal reproductive function. The possibility arises that similar abnormalities in GABA homeostasis may contribute to syndromes of hypothalamic amenorrhea/oligomenorrhea in humans.

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