Abstract
We investigated the distribution patterns of the extracellular matrix protein Reelin and of crucial Reelin signaling components in murine midbrain and striatum. The cellular distribution of the Reelin receptors VLDLr and ApoER2, the intracellular downstream mediator Dab1, and the alternative Reelin receptor APP were analyzed at embryonic day 16, at postnatal stage 15 (P15), and in 3-month-old mice. Reelin was expressed intracellularly and extracellularly in midbrain mesencephalic dopaminergic (mDA) neurons of newborns. In the striatum, Calbindin D-28k+ neurons exhibited Reelin intracellularly at E16 and extracellularly at P15 and 3 months. ApoER2 and VLDLr were expressed in mDA neurons at E16 and P15 and in oligodendrocytes at 3 months, whereas Dab1 and APP immunoreactivity was observed in mDA at all stages analyzed. In the striatum, Calbindin D-28k+/GAD67+ inhibitory neurons expressed VLDLr, ApoER2, and Dab1 at P15, but only Dab1 at E16 and 3 months. APP was always expressed in mouse striatum in which it colocalized with Calbindin D-28k. Our data underline the importance of Reelin signalling during embryonic development and early postnatal maturation of the mesostriatal and mesocorticolimbic system, and suggest that the striatum and not the midbrain is the primary source of Reelin for midbrain neurons. The loss of ApoER2 and VLDLr expression in the mature midbrain and striatum implies that Reelin functions are restricted to migratory events and early postnatal maturation and are dispensable for the maintenance of dopaminergic neurons.
Highlights
At P0, distinct Reelin positivity was detected in the cytoplasm of midbrain neurons and in the adjacent extracellular space (Fig. 1j–o) indicating that Reelin expression in the midbrain was restricted to a relatively small time period, and that Reelin was afterwards stored in extracellular pools
We have further analyzed the expression of the intracellular downstream mediator Dab1 and the alternative Reelin receptor amyloid beta precursor proteins (APP) in the murine midbrain and striatum
We have clearly demonstrated that the Reelin receptors apolipoprotein E receptor type 2 (ApoER2) and very low density lipoprotein receptors (VLDLr) are expressed by tyrosine hydroxylase (TH)+ midbrain neurons at embryonic day 16 (E16) and postnatal stage 15 (P15) but not at 3 months
Summary
Cell Tissue Res (2015) 359:393–407 phosphorylation of Dab, Src-family tyrosine kinases and other non-receptor tyrosine kinases become activated and trigger multiple downstream signaling cascades (Arnaud et al 2003; Jossin et al 2003; Howell et al 1999), leading to the regulation of neuronal migration and neurite outgrowth (Del Río et al 1997; Borrell et al 1999; Niu et al 2004; Beffert et al 2005; Hiesberger et al 1999; Arnaud et al 2003). We have previously described the roles of ApoER2 and VLDLr in the proper migration and positioning of mouse mDA neurons (Sharaf et al 2013). We have investigated the distribution patterns of Reelin signaling pathway components in the murine midbrain and striatum during embryonic, postnatal, and adult stages
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