Reelin controls position of autonomic neurons in the spinal cord

Abstract

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 ...

Interaction between Dab1 and CrkII is promoted by Reelin signaling

“…Many Reelin-responsive neurons fail to meet this criterion, such as Purkinje cells, and some cortical neurons, which do not migrate far enough when Reelin or downstream components of the pathway are missing. However, the preganglionic autonomic spinal cord neurons (AMNs) appear to migrate beyond their target zones in the absence of Reelin (Phelps et al, 2002;Yip et al, 2000). The migratory pathway of these neurons is complex.…”

Analysis of the RELN gene as a genetic risk factor for autism

“…11 Further studies have identified RELN as necessary for proper formation of brain structures by directing migration of neuronal precursors. [12][13][14][15][16][17][18][19] These suggestive developmental roles for RELN correlate with RELN abnormalities in several neurogenetic diseases. RELN mRNA and protein levels are significantly reduced in multiple brain areas of patients with schizophrenia 20,21 and bipolar disorder with psychosis.…”

Reelin signaling directly affects radial glia morphology and biochemical maturation

“…Indeed, radial glia morphology or Blbp content is normal in the spinal cord of reeler mice (data not shown) as is radial cell migration. Interestingly, only the tangential migration of preganglionic neurons is affected in the spinal cord of reelindeficient mice (Yip et al, 2000;Phelps et al, 2002). Thus, the effect of reelin on tangential cell migration seems to be mediated in a radial glia independent manner, potentially by signaling directly to the migrating neurons.…”