The known Duchenne muscular dystrophy (DMD) gene products, the muscle-and brain-type dystrophin isoforms, are 427-kDa proteins translated from 14-kilobase (kb) mRNAs. Recently we described a 6.5-kb mRNA that also is transcribed from the DMD gene. Cloning and in vitro transcription and translation of the entire coding region show that the 6.5-kb mRNA encodes a 70.8-kDa protein that is a major product of the DMD gene. It contains the C-terminal and the cysteine-rich domains of dystrophin, seven additional amino acids at the N terminus, and some modifications formed by alternative splicing in the C-terminal domain. It lacks the entire large domain of spectrin-like repeats and the actinbinding N-terminal domain of dystrophin. This protein is the major DMD gene product in brain and other nonmuscle tissues but is undetectable in skeletal muscle extracts.
We have isolated from mouse skeletal muscle a subpopulation of slow adherent myogenic cells that can proliferate for at least several months as suspended clusters of cells (myospheres). In the appropriate conditions, the myospheres adhere to the plate, spread out, and form a monolayer of MyoD ؉ cells.
The dystrophin gene, which is defective in Duchenne muscular dystrophy (DMD), also encodes a number of smaller products controlled by internal promoters. Dp71, which consists of the two C-terminal domains of dystrophin, is the most abundant product of the gene in non-muscle tissues and is the major product in adult brain. To study the possible function of Dp71 and its expression during development, we specifically inactivated the expression of Dp71 by replacing its first and unique exon and a part of the concomitant intron with a beta-galactosidase reporter gene. X-Gal staining of Dp71-null mouse embryos and tissues revealed a very stage- and cell type-specific activity of the Dp71 promoter during development and during differentiation of various tissues, including the nervous system, eyes, limb buds, lungs, blood vessels, vibrissae and hair follicles. High activity of the Dp71 promoter often seemed to be associated with morphogenic events and terminal differentiation. In some tissues the activity greatly increased towards birth.
Developmental axon pruning is essential for normal brain wiring in vertebrates and invertebrates. How axon pruning occurs in vivo is not well understood. In a mosaic loss-of-function screen, we found that Bsk, the Drosophila JNK, is required for axon pruning of mushroom body γ neurons, but not their dendrites. By combining in vivo genetics, biochemistry, and high-resolution microscopy, we demonstrate that the mechanism by which Bsk is required for pruning is through reducing the membrane levels of the adhesion molecule Fasciclin II (FasII), the NCAM ortholog. Conversely, overexpression of FasII is sufficient to inhibit axon pruning. Finally, we show that overexpressing other cell adhesion molecules, together with weak attenuation of JNK signaling, strongly inhibits pruning. Taken together, we have uncovered a novel and unexpected interaction between the JNK pathway and cell adhesion and found that destabilization of cell adhesion is necessary for efficient pruning.
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