The Cell Adhesion Molecule M-Cadherin Is Not Essential for Muscle Development and Regeneration

Abstract

M-cadherin is a classical calcium-dependent cell adhesion molecule that is highly expressed in developing skeletal muscle, satellite cells, and cerebellum. Based on its expression pattern and observations in cell culture, it has been postulated that M-cadherin may be important for the fusion of myoblasts to form myotubes, the correct localization and function of satellite cells during muscle regeneration, and the specialized architecture of adhering junctions in granule cells of cerebellar glomeruli. In order to investigate the potential roles of M-cadherin in vivo, we generated a null mutation in mice. Mutant mice were viable and fertile and showed no gross developmental defects. In particular, the skeletal musculature appeared essentially normal. Moreover, muscle lesions induced by necrosis were efficiently repaired in mutant mice, suggesting that satellite cells are present, can be activated, and are able to form new myofibers. This was also confirmed by normal growth and fusion potential of mutant satellite cells cultured in vitro. In the cerebellum of M-cadherin-lacking mutants, typical contactus adherens junctions were present and similar in size and numbers to the equivalent junctions in wild-type animals. However, the adhesion plaques in the cerebellum of these mutants appeared to contain elevated levels of N-cadherin compared to wild-type animals. Taken together, these observations suggest that M-cadherin in the mouse serves no absolutely required function during muscle development and regeneration and is not essential for the formation of specialized cell contacts in the cerebellum. It seems that N-cadherin or other cadherins can largely compensate for the lack of M-cadherin.

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

“…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). …”

“…The nature of the small fraction of cells expressing P-cadherin remains unknown. Previous studies (Hollnagel et al, 2002) noted that this cadherin is not expressed in postmitotic neurons of the cerebellar granule cell layer. Consistently, we find that this set of cells comprises a substantial subset of mitotically active cells.…”

“…Further, cells expressing these cadherins are highly proliferative (table 2), as expected for cerebellar vascular endothelia which rapidly expand during the first two postnatal weeks (Acker et al, 2001). Math1-EGFP negative granule cells in contrast are postmitotic, and have previously been reported to be negative for these cadherins (Rose et al, 1995;Hollnagel et al, 2002;Alva et al, 2006). The nature of the small fraction of cells expressing P-cadherin remains unknown.…”

“…Cells immunopositive for E-cadherin and cadherin-5, and, to a lesser degree, those positive for P-cadherin, comprised a much greater complement of cells in S/G 2 /M phase (i.e. were considerably more mitotically active) than the average of all Math1-EGFP-negative cells or cells positive for M-and Ncadherin, which have previously been shown to be expressed in granule cells (Rose et al, 1995;Hollnagel et al, 2002). Cells immunoreactive for R-cadherin comprise intermediate numbers of cells in S/G 2 /M phase.…”

“…These cadherins were selected based on previous reports on their expression in the cerebellar anlage (Luckner et al, 2001;Hollnagel et al, 2002;Liu et al, 2004) and the availability of specific antibodies suitable for flow cytometric analysis. We focused on cells isolated from postnatal day 8 cerebella because they contain sizable complements of granule cells in various stages of differentiation as well as of other cerebellar cells, the developmental state of which is reasonably well characterized.…”