T he autosomal recessive mouse mutant reeler, which exhibits ataxia of gait, dystonic posture, and tremor (1), has provided a genetic model for neural development for half a century (2-4). Characteristic of the reeler mutant are abnormal lamination of the cerebral, cerebellar, and hippocampal cortices and neuronal ectopia in several brainstem nuclei (5-13). The gene Reln, the mutation of which is responsible for the reeler phenotype, has recently been cloned (14). Its protein product, reelin, has been identified as an extracellular matrix molecule (15). Despite such progress, the role of reelin in neuronal migration remains unknown. The migration of sympathetic preganglionic neurons reported here provides a simple model system that could facilitate studies of reelin function.Sympathetic preganglionic neurons undergo extensive migration during the development of the spinal cord. In the rat (16-18), it has been shown that postmitotic preganglionic neurons first migrate from the neuroepithelium along radial glial fibers to the ventrolateral spinal cord. There, along with somatic motor neurons, they form a primitive motor column. Preganglionic neurons next segregate from the somatic motor neurons and undergo a secondary dorsolateral migration toward the intermediolateral column (IML) region. This secondary migration is perpendicular to radial fibers and is independent of radial glial fibers. Upon terminal migration, the majority of preganglionic neurons become localized to the IML. A small number of preganglionic neurons settle in areas adjacent to the central canal.Results from our present study show that the migration of preganglionic neurons in the reeler mutant is disrupted. Moreover, reelin expression and in vitro function blocking studies suggest that reelin acts as a barrier to migrating preganglionic neurons. Materials and MethodsAnimals. The reeler mouse colony was originally derived from heterozygous B6C3Fe-a͞a-rl adults (The Jackson Laboratory). Homozygous and heterozygous mice were obtained by mating homozygous males with heterozygous females. The day on which a vaginal plug was detected was designated as embryonic day 0.5 (E0.5). Embryonic staging was verified by using the criteria of Rugh (19). Embryos were genotyped by using PCR (20).Sympathetic Nervous System of the Mouse. The anatomy of the sympathetic nervous system is shown in Fig. 1. Sympathetic preganglionic neurons are located primarily in the IML region of the thoracic spinal cord. Their axons exit the spinal cord in the ventral roots to enter into the paravertebral ganglia. Most preganglionic axons terminate in the paravertebral ganglia. Some axons pass through the paravertebral ganglia to innervate the prevertebral ganglia. Postganglionic neurons innervate smooth muscle, cardiac muscle, and glands. Identification of Preganglionic Neurons in the Mouse Embryo.Preganglionic neurons in embryos were retrogradely labeled with 1,1Ј-dioctadecyl-3,3,3Ј,3Ј-tetramethylindocarbocyanine (DiI) or fluorescent dextran amines (Molecular Probes). For dextran ...
In the spinal ganglia of the chick embryo, two neuronal populations can be distinguished:large, early differentiating ventrolateral (VL) cells and small, late differentiating dorsomedial (DM) cells. It was found that, beginning with stage 25, the DM cells originate from a narrow band of small, immature cells at the medial border of the ganglion, extending to the dorsolateral border. We have designated this band as the inner and outer marginal zone.Neuronal death was investigated in thoracic ganglion 18 and brachial ganglion 15 by counting degenerating cells, separately for the VL and DM populations, at every stage from stage 24 (4% days) to stage 38 (12 days). In both ganglia, separate degeneration periods were found for the VL and DM populations which do not overlap. The peaks of degeneration are: stage 27 (5% days) for the VL population in ganglion 18, stage 30 (6% to 7 days) for VL in ganglion 16, and stage 35 (8% days) for DM in both ganglia.Daily injections of 6 pg of nerve growth factor, (NGF) in 6 to 12 ~1 of 0.9% sterile salt solution into the yolk sac from stage 21 (3% days) to the day of sacrifice resulted in a significant reduction of neuronal death in the VL population of ganglion 18 and in the rescue of practically all VL neurons in ganglion 15 and all DM neurons in both ganglia, which normally would have died. This is the first demonstration of an NGF effect on VL neurons.In the analysis of the multiple effects of nerve growth factor (NGF), the sympathetic ganglia have played the dominant role; the sensory ganglia which are the other target of NGF have attracted much less attention. Yet, if one entertains the notion that NGF might be the natural trophic maintenance agent for these two neuron types (i.e., that NGF is actually produced by their target organs), then one approach to the testing of this hypothesis would be to engage in in viva experiments.For this ' Dedicated to Dr. Rita Levi-Montalcini.
SUMMARY1. Synapses by flexor nerve were induced on denervated extensor muscle in adult salamander forelimbs. Excitatory potentials evoked by these 'foreign' synapses were at first small but increased to normal amplitude within several weeks, in the absence of correct nerve reinnervation.2. Upon return of the correct nerve the efficacy of foreign synaptic transmission began to decline. The time of initiation of this decline correlated well with the resumption of correct nerve transmission. The suppression of foreign transmission involved a reduction in mean quantal content of transmitter release.3. Suppression of foreign synapses was sufficiently thorough that most ceased transmitting entirely. Before reinnervation by the correct nerve 97 % of the extensor muscle fibres received functional foreign synapses while 4-6 months after correct nerve return only 35 % ofthe fibres retained foreign synapses, with weak transmission.4. Two lines of evidence indicate that suppressed foreign synapses are lost from the muscle: (a) a second correct nerve lesion 6-8 months after the initial denervation produced no significant increase in the proportion of fibres with foreign transmission and (b) four muscles which showed complete suppression offoreign transmission were bathed in medium containing horseradish peroxidase (h.r.p.) and the correct nerve was stimulated repetitively. Subsequent histochemical staining for h.r.p. and examination of synapses by electron microscopy revealed that 94 % of the axon terminals had h.r.p. incorporated in vesicles. Thus at least that percentage of all identifiable synapses were from the correct nerve.5. This ability to eliminate incorrect synapses in favour of correct ones is speculated to be a general characteristic of embryonic nervous systems, which in adulthood is retained by salamanders but lost by most other animals.
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