Localized deposition of M‐cadherin in the glomeruli of the granular layer during the postnatal development of mouse cerebellum

Abstract

M-cadherin is a Ca2+-dependent cell adhesion molecule of the cadherin family, initially localized at the areas of contact between myotubes during myogenesis, but also detected in the peripheral nerve and at the adult neuromuscular junction. In this study, searching for the expression of M-cadherin in the adult mouse brain, we observed a restricted expression of M-cadherin in one of the three layers of the cerebellar cortex: the granular layer. M-cadherin was accumulated in structures rich in synapses and other intercellular junctions where mossy fibers connect granule cell dendrites, the glomeruli. This molecule was not expressed in the cerebellum during the first steps of postnatal cerebellar neurogenesis: granule cell proliferation and migration and Purkinje cell alignment. M-cadherin expression was first detected at postnatal day (P) 11, after the establishment of the synaptic connections between mossy fibers and granule cell dendrites. It then accumulated in glomeruli during their phase of maturation which is characterized by the formation of puncta adherentia between granule cell dendrites. M-cadherin was undetectable in the cerebella of the weaver and staggerer mutants, lacking granule cells, and therefore mature glomeruli and puncta adherentia. Furthermore, other components classically associated with intercellular junctions, i.e., alpha-caterin, beta-catenin and actin filaments, closely paralleled M-cadherin appearance and colocalized with M-cadherin in the mature glomeruli. M-cadherin, which appears as a molecular marker of glomerulus maturation, might be implicated in the formation, and be the ligand, of adherens junctions encountered in this structure.

Expression of classical cadherins in the cerebellar anlage: Quantitative and functional aspects

“…Our analysis of the expression of a sizable set of cadherins in the developing cerebellum extends previous observations (e.g., Arndt et al, 1998;Luckner et al, 2001;Moore et al, 2004;Bahjaoui-Bouhaddi et al, 1997) in three substantial ways: First, multi-parameter flow cytometric analysis allowed us to derive a quantitative assessment of cadherin expression in molecularly defined cerebellar phenotypes. Second, we were able to correlate quantitative changes in cadherin expression with the developmental progression of granule cells.…”

“…Such heterogeneity is also reflected by the differential expression of a set of other molecular markers in the nascent cerebellar cortex (Mellor et al, 1998;Kuhar et al, 1993;Schilling et al, 1994). The developmental increase in the expression of M-, N-and R-cadherin documented by the inverse correlation of their levels with those of Math1-EGFP is consistent with qualitative data on expression of these cadherins in the cerebellar anlage (M: Bahjaoui-Bouhaddi et al, 1997;N: Redies and Takeichi, 1993;Hollnagel et al, 2002;R: Liu et al, 2004;Arndt and Redies, 1996;Luckner et al, 2001). …”

“…No signal was detected for cadherins-6, -12 and -20. The age-related increase in M-cadherin signal reflects the developmental up-regulation of this gene described before (Bahjaoui-Bouhaddi et al, 1997). (D) Fluorescence intensity averaged over the complete area covered by panels A-C for the EGFP (green line) and the nuclear (red line) signals, and the ratio of the EGFP relative to the nuclear signal (i.e., the EGFP signal normalized to the cell density; black line).…”

“…They are fully consistent with information about the expression of this class of molecules within the cerebellum published to date. E.g., although our PCR analysis is clearly not quantitative, it reflects the developmental increase in Mcadherin expression which parallels granule cell synaptic integration (Rose et al, 1995;Bahjaoui-Bouhaddi et al, 1997). We next sought to analyze, on the level of protein expression, changes of cadherin expression in molecularly defined subsets of developing cerebellar neurons.…”

“…Histogenesis of the cerebellar cortex has been described in quite some detail (e.g., Altman and Bayer, 1997;Goldowitz and Hamre, 1998;Sotelo, 2004), and maturation and differentiation of individual cerebellar cells may be related by their expression of a host of specific molecular markers (e.g., Oberdick et al, 1998;Wang and Zoghbi, 2001). Several cadherins have been found to be expressed in the cerebellum and its anlage (e.g., Arndt et al, 1998;Luckner et al, 2001;Moore et al, 2004;Bahjaoui-Bouhaddi et al, 1997;Liu et al, 2004;Fushimi et al, 1997), and deletion of αN-catenin, which is involved in linking the classical cadherins to the neuronal cytoskeleton, shows a severe cerebellar phenotype (Park et al, 2002). Thus, the cerebellum provides a promising paradigm to further address the significance of cadherin expression for nervous system development and patterning.…”