Abstract
Developing skeletal myofibers in vertebrates are intrinsically 'pre-patterned' for motor nerve innervation. However, the intrinsic factors that regulate muscle pre-patterning remain unknown. We found that a functional skeletal muscle dihydropyridine receptor (DHPR, the L-type Ca(2+) channel in muscle) was required for muscle pre-patterning during the development of the neuromuscular junction (NMJ). Targeted deletion of the β1 subunit of DHPR (Cacnb1) in mice led to muscle pre-patterning defects, aberrant innervation and precocious maturation of the NMJ. Reintroducing Cacnb1 into Cacnb1(-/-) muscles reversed the pre-patterning defects and restored normal development of the NMJ. The mechanism by which DHPRs govern muscle pre-patterning is independent of their role in excitation-contraction coupling, but requires Ca(2+) influx through the L-type Ca(2+) channel. Our findings indicate that the skeletal muscle DHPR retrogradely regulates the patterning and formation of the NMJ.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Body Patterning / genetics
-
Body Patterning / physiology*
-
CD24 Antigen / genetics
-
Calcium / metabolism
-
Calcium Channels, L-Type / deficiency
-
Calcium Channels, L-Type / physiology*
-
Cell Line, Transformed
-
Electron Microscope Tomography / methods
-
Embryo, Mammalian
-
Excitatory Postsynaptic Potentials / genetics
-
Homeodomain Proteins
-
Humans
-
Male
-
Mice
-
Mice, Knockout
-
Muscle, Skeletal / embryology*
-
Neuromuscular Junction / embryology*
-
Neuromuscular Junction / genetics
-
Neuromuscular Junction / physiology*
-
Neuromuscular Junction / ultrastructure
-
Receptor Protein-Tyrosine Kinases / metabolism
-
Receptors, Nicotinic / metabolism
-
Transcription Factors / deficiency
-
Up-Regulation / genetics
Substances
-
CD24 Antigen
-
Cacnb1 protein, mouse
-
Calcium Channels, L-Type
-
Cd24a protein, mouse
-
Homeodomain Proteins
-
Receptors, Nicotinic
-
Transcription Factors
-
Hb9 protein, mouse
-
MuSK protein, mouse
-
Receptor Protein-Tyrosine Kinases
-
Calcium