Migratory defect of mesencephalic dopaminergic neurons in developingreelermice

Abstract

Reelin, an extracellular glycoprotein has an important role in the proper migration and positioning of neurons during brain development. Lack of reelin causes not only disorganized lamination of the cerebral and cerebellar cortex but also malpositioning of mesencephalic dopaminergic (mDA) neurons. However, the accurate role of reelin in the migration and positioning of mDA neurons is not fully elucidated. In this study, reelin-deficient reeler mice exhibited a significant loss of mDA neurons in the substantia nigra pars compacta (SNc) and a severe alteration of cell distribution in the retrorubal field (RRF). This abnormality was also found in Dab1-deficinet, yotari mice. Stereological analysis revealed that total number of mDA neurons was not changed compared to wild type, suggesting that the loss of mDA neurons in reeler may not be due to the neurogenesis of mDA neurons. We also found that formation of PSA-NCAM-positive tangential nerve fibers rather than radial glial fibers was greatly reduced in the early developmental stage (E14.5) of reeler. These findings provide direct evidence that the alteration in distribution pattern of mDA neurons in the reeler mesencephalon mainly results from the defect of the lateral migration using tangential fibers as a scaffold.

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).…”

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).…”

“…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). Moreover, the RELN receptors LRP8 (low density lipoprotein receptor-related protein 8, also known as ApoER2) and VLDLR (very low density lipoprotein receptor) are also required for the migration and final positioning of mDA neurons (Sharaf et al, 2013).…”