Lack of Reelin causes malpositioning of nigral dopaminergic neurons: Evidence from comparison of normal and Reln^rl mutant mice

Abstract

The reeler gene (Reln(rl), formerly rl) product Reelin controls neuronal migration and positioning and thereby plays a key role in brain development. Mutation of Reln leads to widespread disruption of laminar cortical regions and ectopia in some brainstem nuclei. In the embryonic striatum of normal mice, a substantial expression of reelin mRNA has been documented; however, the anomalous positioning of neurons in the basal ganglia of reeler mice remains to be studied. We provide first evidence for a potential role of Reelin in the developmental formation of the substantia nigra. In reeler mutant mice lacking Reelin, dopaminergic neurons destined for the substantia nigra fail to migrate laterally and become anomalously clustered just lateral to the ventral tegmental area. Their axons appear to project to striatal patches forming "dopamine islands." Results from the normal mice show that, at the midembryonic stage, Reelin identified with CR-50 is highly concentrated in the ventral mesencephalon, where nigral dopaminergic neurons are in progress to migrate laterally to their eventual position of the adult brain. A combination of CR-50 labeling and anterograde axonal tracing provided evidence that embryonic striatal neurons may supply the ventral portion of the mesencephalon with Reelin through their axonal projections. We hypothesize that Reelin plays a role in the positioning of nigral dopaminergic neurons and that it can act as an environmental cue at a remote site far from its birthplace via a transaxonal delivery system.

Reelin and CXCL12 regulate distinct migratory behaviors during the development of the dopaminergic system

“…Previous studies proposed that the SN does not form in Reeler mutants (Kang et al, 2010;Nishikawa et al, 2003). We show here that in Reeler as well as in Dab1 KO and Apoer2/Vldlr double KO mutants, the lack of lateral dispersion of SN neurons is confined to intermediate levels, whereas the anterior SN is merely disorganized (see also Sharaf et al, 2013).…”

“…The reelin pathway could play a role in regulating tangential migration of DA neurons, as it has been reported that the SN does not form in Reeler mutants (Kang et al, 2010;Nishikawa et al, 2003;Trommsdorff et al, 1999). Reelin, a large extracellular glycoprotein, regulates migration in several brain areas and signals via the transmembrane receptors APOER2 (APOE receptor 2; LRP8 -Mouse Genome Informatics) and VLDLR (very low density lipoprotein receptor) and the downstream effector DAB1 (disabled 1) (D'Arcangelo et al, 1999;Rice et al, 1998).…”

“…Markers that are expressed specifically in SN, VTA or RRF neurons throughout their development have not been identified, hampering the characterization of distinct DA migratory paths and the identification of the molecular mechanisms that regulate DA neuronal migration. Based on loss-of-function mouse mutants in which the formation of the SN and/or VTA is impaired, only the netrin receptor DCC (deleted in colorectal carcinoma), the extracellular glycoprotein reelin, and the cell adhesion molecule L1 (L1CAM -Mouse Genome Informatics) have been implicated in the regulation of DA neuronal migration (Ballmaier et al, 2002;Demyanenko et al, 2001;Kang et al, 2010;Nishikawa et al, 2003).…”

Ventral Mesencephalon-Enriched Genes That Regulate the Development of Dopaminergic NeuronsIn Vivo

“…Thus the timing for striatal dysplasia occurs much later than the deficiency in SN formation. Third, reelin has been reported to be produced in the striatum and transported to the SN (Nishikawa et al, 2003). We found that reelin expression was not altered in either the striatum or the SN…”

How to make a midbrain dopaminergic neuron

“…Whereas pharmacological inhibition or deletion of Cxcr4 does not affect the number of mDA neurons, it affects their migration, as some cells remain in the IZ and do not reach the MZ (Yang et al, 2013b). Tangential migration of mDA neurons is regulated by the neural L1 cell adhesion molecule (L1CAM) (Demyanenko et al, 2001;Ohyama et al, 1998) and RELN (reelin) (Kang et al, 2010;Nishikawa et al, 2003). Mice lacking Reln or the cytoplasmic adaptor protein Dab1 (disabled 1) have fewer PSA-NCAM + tangential fibers and fewer mDA neurons reaching the SNc, despite normal numbers of mDA neurons being generated (Kang et al, 2010).…”