Authors: WANG, DONGQING¹; KELLY, BRIDGET B.¹; ALBRECHT, DOUGLAS E.²; ADAMS, MARVIN E.²; FROEHNER, STANLEY C.²; FENG, AND GUOPING³

Source: Gene Expression, Volume 14, Number 1, 2007 , pp. 47-57(11)

Publisher: Cognizant Communication Corporation

Abstract:

The dystrophin glycoprotein complex (DGC) is critical for muscle stability, and mutations in DGC proteins lead to muscular dystrophy. The DGC also contributes to the maturation and maintenance of the neuromuscular junction (NMJ). The gene encoding the DGC protein α-dystrobrevin undergoes alternative splicing to produce at least five known isoforms. Isoform-specific antibody staining and reverse transcription PCR in mutant mice with a deletion of exon 3 of the α-dystrobrevin gene suggested the existence of a remaining synaptic isoform, which might be compensating for α-dystrobrevin function. To test this possibility and to more completely understand the synaptic function of α-dystrobrevin, we used a two-step homologous recombination strategy combined with in vivo Cre-mediated excision to generate mice with a large deletion of the α-dystrobrevin gene to disrupt all isoforms. However, these mice did not exhibit a more severe NMJ phenotype than that observed in the exon 3-deleted mice. Nonetheless, these mice not only eliminate possible compensation by remaining isoforms of α-dystrobrevin, but also offer a conditional allele that could be used to identify tissue-specific and developmental functions of α-dystrobrevin. This work also demonstrates a successful strategy to achieve deletion of a large genomic sequence, which can be a valuable tool for functional studies of genes encoding multiple isoforms that span a large genomic region.

Keywords: Dystrophin glycoprotein complex; Neuromuscular junction; Isoform diversity; Alternative splicing; Homologous recombination

Document Type: Research article

Affiliations: 1: Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA 2: Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195, USA 3: Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA, Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA

Publication date: 2007-01-01

More about this publication?

• The Molecular and Cellular Biology area of Gene Expression covers all aspects of the gene including it structure, functions, and regulation in prokaryotes, eukaryotes, and viruses; molecular and cell biological aspects of cell growth and development, chromatin structure and function. These include topics such as DNA replication, DNA repair, gene transcription, transcriptional control, RNA processing, posttranscriptional control, oncogenes, molecular mechanisms of action of hormones, molecular mechanism of cellular differentiation, growth and development, protein synthesis, and posttranslational control.
  The Molecular and Cellular Neuroscience area of Gene Expression covers all aspects of gene expression as described but is devoted exclusively to the nervous system in health and disease. Topics include studies of neurogenesis, development, aging, and neurodegeneration. Complex neural systems, motor control, special senses, and higher cortical function, when viewed from the perspective of gene expression, are appropriate for the journal. Research related to molecular mechanisms of drug tolerance, dependence, and withdrawal are solicited. Manuscripts on state-of-the-art methods and protocols for molecular profiling of neuronal structure and function are welcome.

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