Developmental expression of BPAG1-n: insights into the spastic ataxia and gross neurologic degeneration in dystonia musculorum mice.
Ablation of the BPAG1 gene results in the dystonia musculorum mouse, exhibiting rapid spinal nerve degeneration, dystonic movements, and severe ataxia. By defining the developmental and tissue-specific expression of the neuronal form of BPAG1 (BPAG1-n) and by comparing the corresponding pathology in BPAG1 null mice, we seek here to understand how absence of BPAG1 results in this devastating phenotype in mice and in potentially related human neurological disorders. Throughout normal development, BPAG1-n was expressed in a variety of sensory and autonomic neuronal structures, but was absent or reduced in areas such as basal ganglia that are often affected in dystonias and ataxias. Interestingly, BPAG1-n was also expressed broadly in embryonic motor neurons, but expression declined dramatically after birth. Despite these complex developmental patterns, BPAG1-/- pathology was restricted largely to postnatal development. Moreover, gross neuronal degeneration was restricted to only a few regions where BPAG1-n was found, including dorsal root ganglion neurons and a small subset of motor neurons. Most notably, while skeletal muscle was normal, appearance of severe dystonic ataxia correlated with postnatal degeneration of muscle spindles. Collectively, our findings suggest a mechanism for the BPAG1 null phenotype and indicate that different neurons respond differently to the absence of BPAG1-n, a cytoskeletal linker protein.
Dowling
J
J
Department of Molecular Genetics and Cell Biology, Howard Hughes Medical Institute, Chicago, Illinois 60637, USA.
Yang
Y
Y
Wollmann
R
R
Reichardt
L F
LF
Fuchs
E
E
D000818:Animals; D001259:Ataxia / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D001324:Autoantigens / Q000096:biosynthesis* / Q000235:genetics; D001479:Basal Ganglia / Q000737:chemistry / Q000473:pathology; D002352:Carrier Proteins; D002531:Cerebellum / Q000737:chemistry / Q000473:pathology; D003094:Collagen; D003598:Cytoskeletal Proteins; D000071821:Dystonin; D051379:Mice; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000294:innervation; D009410:Nerve Degeneration / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D009420:Nervous System / Q000196:embryology; D009422:Nervous System Diseases / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D009475:Neurons, Afferent / Q000737:chemistry / Q000473:pathology; D024041:Non-Fibrillar Collagens; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D013116:Spinal Cord / Q000737:chemistry / Q000473:pathology; D014018:Tissue Distribution; D000097805:Collagen Type XVII
D001324:Autoantigens; D002352:Carrier Proteins; D003094:Collagen; D003598:Cytoskeletal Proteins; D000071821:Dystonin; D009419:Nerve Tissue Proteins; D024041:Non-Fibrillar Collagens; D012333:RNA, Messenger; D000097805:Collagen Type XVII; C486268:DST protein, human; C095667:Dst protein, mouse