RESUMO
Actin filaments (F-actin) are key components of sarcomeres, the basic contractile units of skeletal muscle myofibrils. A crucial step during myofibril differentiation is the sequential exchange of α-actin isoforms from smooth muscle (α-SMA) and cardiac (α-CAA) to skeletal muscle α-actin (α-SKA) that, in mice, occurs during early postnatal life. This "α-actin switch" requires the coordinated activity of actin regulators because it is vital that sarcomere structure and function are maintained during differentiation. The molecular machinery that controls the α-actin switch, however, remains enigmatic. Cyclase-associated proteins (CAP) are a family of actin regulators with largely unknown physiological functions. We here report a function for CAP2 in regulating the α-actin exchange during myofibril differentiation. This α-actin switch was delayed in systemic CAP2 mutant mice, and myofibrils remained in an undifferentiated stage at the onset of the often excessive voluntary movements in postnatal mice. The delay in the α-actin switch coincided with the onset of motor function deficits and histopathological changes including a high frequency of type IIB ring fibers. Our data suggest that subtle disturbances of postnatal F-actin remodeling are sufficient for predisposing muscle fibers to form ring fibers. Cofilin2, a putative CAP2 interaction partner, has been recently implicated in myofibril actin cytoskeleton differentiation, and the myopathies in cofilin2 and CAP2 mutant mice showed striking similarities. We therefore propose a model in which CAP2 and cofilin2 cooperate in actin regulation during myofibril differentiation.
Assuntos
Citoesqueleto de Actina/fisiologia , Proteínas de Transporte , Diferenciação Celular , Músculo Esquelético , Miofibrilas/fisiologia , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/fisiologia , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Feminino , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Masculino , Camundongos , Camundongos Knockout , Desenvolvimento Muscular/genética , Desenvolvimento Muscular/fisiologia , Músculo Esquelético/citologia , Músculo Esquelético/fisiologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMO
BACKGROUND: The interstitial 6p22.3 deletions concern rare chromosomal events affecting numerous aspects of both physical and mental development. The syndrome is characterized by partial deletion of chromosome 6, which may arise in a number of ways. CASE PRESENTATION: We report a 2.8-year old boy presenting with developmental delay and mild dysmorphisms. High-resolution oligonucleotide microarray analysis revealed with high precision a 2.5 Mb interstitial 6p deletion in the 6p22.3 region which encompasses 13 genes. CONCLUSIONS: Identification and in-depth analysis of cases presenting with mild features of the syndrome will sharpen our understanding of the genetic spectrum of the 6p22.3 deletion.