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The BPAG1 locus: Alternative splicing produces multiple isoforms with distinct cytoskeletal linker domains, including predominant isoforms in neurons and muscles.

Leung CL, Zheng M, Prater SM, Liem RK - J. Cell Biol. (2001)

Bottom Line: We have analyzed the BPAG1 locus in detail and found that it encodes different interaction domains that are combined in tissue-specific manners.BPAG1-a is composed of the ABD, the plakin domain, the SR-containing rod domain, and the MTBD.BPAG1-b is highly expressed in muscles, and has extra exons encoding a second IFBD between the plakin and SR-containing rod domains of BPAG1-a.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.

ABSTRACT
Bullous pemphigoid antigen 1 (BPAG1) is a member of the plakin family with cytoskeletal linker properties. Mutations in BPAG1 cause sensory neuron degeneration and skin fragility in mice. We have analyzed the BPAG1 locus in detail and found that it encodes different interaction domains that are combined in tissue-specific manners. These domains include an actin-binding domain (ABD), a plakin domain, a coiled coil (CC) rod domain, two different potential intermediate filament-binding domains (IFBDs), a spectrin repeat (SR)-containing rod domain, and a microtubule-binding domain (MTBD). There are at least three major forms of BPAG1: BPAG1-e (302 kD), BPAG1-a (615 kD), and BPAG1-b (834 kD). BPAG1-e has been described previously and consists of the plakin domain, the CC rod domain, and the first IFBD. It is the primary epidermal BPAG1 isoform, and its absence that is the likely cause of skin fragility in mutant mice. BPAG1-a is the major isoform in the nervous system and a homologue of the microtubule actin cross-linking factor, MACF. BPAG1-a is composed of the ABD, the plakin domain, the SR-containing rod domain, and the MTBD. The absence of BPAG1-a is the likely cause of sensory neurodegeneration in mutant mice. BPAG1-b is highly expressed in muscles, and has extra exons encoding a second IFBD between the plakin and SR-containing rod domains of BPAG1-a.

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In situ hybridization of E14.5 embryos. (A) Sagittal section of mouse embryo hybridized with probe specific for the IFBD1. Hybridization signal was detected in the skin (short arrow) and mucosal epithelia of the digestive tract (long arrow). The weaker signal inside the trunk was apparently background hybridization, since it did not display any structural pattern. An identical hybridization pattern was obtained with a probe against the CC rod domain. (B) Sagittal section of mouse embryo hybridized with probe specific for the IFBD2. Strong hybridization signal was detected in the tongue (long arrow), heart (▸), skeletal muscle masses at the back (short arrow), and bone cartilage of the vertebrae (▹). Background hybridization was also apparent in the trunk. (C) Sagittal section of mouse embryo hybridized with probe specific for the MTBD. Similar hybridization patterns were also found with probes against the SR-containing rod domain and the ABD. High expression levels of BPAG1 isoforms that contain these domains were observed in the tongue (long arrow), the thymus (▸), and bone cartilage of the vertebrae (▹). In the nervous system, particularly strong signal was detected at the pituitary primordium (short arrow). Adjacent transverse sections hybridized with probes against the CC rod domain (D), IFBD1 (E), and MT-binding domain (F). Probes against the CC rod domain and IFBD1 detected BPAG1-e mRNA in the skin only. BPAG1-a labeled by the MTBD probe is highly expressed in the DRG (arrow). Bars: (A–C) 2 mm; (D–F) 0.5 mm.
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fig4: In situ hybridization of E14.5 embryos. (A) Sagittal section of mouse embryo hybridized with probe specific for the IFBD1. Hybridization signal was detected in the skin (short arrow) and mucosal epithelia of the digestive tract (long arrow). The weaker signal inside the trunk was apparently background hybridization, since it did not display any structural pattern. An identical hybridization pattern was obtained with a probe against the CC rod domain. (B) Sagittal section of mouse embryo hybridized with probe specific for the IFBD2. Strong hybridization signal was detected in the tongue (long arrow), heart (▸), skeletal muscle masses at the back (short arrow), and bone cartilage of the vertebrae (▹). Background hybridization was also apparent in the trunk. (C) Sagittal section of mouse embryo hybridized with probe specific for the MTBD. Similar hybridization patterns were also found with probes against the SR-containing rod domain and the ABD. High expression levels of BPAG1 isoforms that contain these domains were observed in the tongue (long arrow), the thymus (▸), and bone cartilage of the vertebrae (▹). In the nervous system, particularly strong signal was detected at the pituitary primordium (short arrow). Adjacent transverse sections hybridized with probes against the CC rod domain (D), IFBD1 (E), and MT-binding domain (F). Probes against the CC rod domain and IFBD1 detected BPAG1-e mRNA in the skin only. BPAG1-a labeled by the MTBD probe is highly expressed in the DRG (arrow). Bars: (A–C) 2 mm; (D–F) 0.5 mm.

Mentions: To extend our studies on the distribution of BPAG1 isoforms during development, we used probes corresponding to various domains of BPAG1 for in situ hybridization analysis on mouse embryonic day E14.5 embryos. The hybridization patterns of probes against the CC rod domain and IFBD1 were identical, as both labeled the epidermis and mucosal epithelia along the digestive tract (Fig. 4 A and unpublished data). These probes gave no signal in the nervous system, confirming that the BPAG1-n isoforms were not expressed in detectable quantities. The IFBD2 probe specifically labeled BPAG1-b mRNA in myocardium, skeletal muscle masses, vertebrae cartilage, and epithelia of the tongue (Fig. 4 B). More ubiquitous labeling patterns were observed with probes prepared for the ABD, plakin domain, SR-containing rod domain, and MTBD that would label BPAG1-a and BPAG1-b (Fig. 4 C and unpublished data). Strong signals were found with these probes in nervous tissues, especially at the pituitary primordium, the cranial ganglia, and the dorsal root ganglia (DRG). To determine the major form of BPAG1 expressed in the DRG, we hybridized a series of adjacent transverse sections with probes against various domains. Hybridization signals were obtained only with probes against the ABD, plakin domain, SR-containing rod domain, and MTBD, but not with the CC rod domain, IFBD1, and IFBD2 probes. These results demonstrated that BPAG1-e, BPAG1-n, and BPAG1-b are not expressed in high quantities in the DRG, and that the major form there is BPAG1-a (Fig. 4, D–F, and unpublished data).


The BPAG1 locus: Alternative splicing produces multiple isoforms with distinct cytoskeletal linker domains, including predominant isoforms in neurons and muscles.

Leung CL, Zheng M, Prater SM, Liem RK - J. Cell Biol. (2001)

In situ hybridization of E14.5 embryos. (A) Sagittal section of mouse embryo hybridized with probe specific for the IFBD1. Hybridization signal was detected in the skin (short arrow) and mucosal epithelia of the digestive tract (long arrow). The weaker signal inside the trunk was apparently background hybridization, since it did not display any structural pattern. An identical hybridization pattern was obtained with a probe against the CC rod domain. (B) Sagittal section of mouse embryo hybridized with probe specific for the IFBD2. Strong hybridization signal was detected in the tongue (long arrow), heart (▸), skeletal muscle masses at the back (short arrow), and bone cartilage of the vertebrae (▹). Background hybridization was also apparent in the trunk. (C) Sagittal section of mouse embryo hybridized with probe specific for the MTBD. Similar hybridization patterns were also found with probes against the SR-containing rod domain and the ABD. High expression levels of BPAG1 isoforms that contain these domains were observed in the tongue (long arrow), the thymus (▸), and bone cartilage of the vertebrae (▹). In the nervous system, particularly strong signal was detected at the pituitary primordium (short arrow). Adjacent transverse sections hybridized with probes against the CC rod domain (D), IFBD1 (E), and MT-binding domain (F). Probes against the CC rod domain and IFBD1 detected BPAG1-e mRNA in the skin only. BPAG1-a labeled by the MTBD probe is highly expressed in the DRG (arrow). Bars: (A–C) 2 mm; (D–F) 0.5 mm.
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fig4: In situ hybridization of E14.5 embryos. (A) Sagittal section of mouse embryo hybridized with probe specific for the IFBD1. Hybridization signal was detected in the skin (short arrow) and mucosal epithelia of the digestive tract (long arrow). The weaker signal inside the trunk was apparently background hybridization, since it did not display any structural pattern. An identical hybridization pattern was obtained with a probe against the CC rod domain. (B) Sagittal section of mouse embryo hybridized with probe specific for the IFBD2. Strong hybridization signal was detected in the tongue (long arrow), heart (▸), skeletal muscle masses at the back (short arrow), and bone cartilage of the vertebrae (▹). Background hybridization was also apparent in the trunk. (C) Sagittal section of mouse embryo hybridized with probe specific for the MTBD. Similar hybridization patterns were also found with probes against the SR-containing rod domain and the ABD. High expression levels of BPAG1 isoforms that contain these domains were observed in the tongue (long arrow), the thymus (▸), and bone cartilage of the vertebrae (▹). In the nervous system, particularly strong signal was detected at the pituitary primordium (short arrow). Adjacent transverse sections hybridized with probes against the CC rod domain (D), IFBD1 (E), and MT-binding domain (F). Probes against the CC rod domain and IFBD1 detected BPAG1-e mRNA in the skin only. BPAG1-a labeled by the MTBD probe is highly expressed in the DRG (arrow). Bars: (A–C) 2 mm; (D–F) 0.5 mm.
Mentions: To extend our studies on the distribution of BPAG1 isoforms during development, we used probes corresponding to various domains of BPAG1 for in situ hybridization analysis on mouse embryonic day E14.5 embryos. The hybridization patterns of probes against the CC rod domain and IFBD1 were identical, as both labeled the epidermis and mucosal epithelia along the digestive tract (Fig. 4 A and unpublished data). These probes gave no signal in the nervous system, confirming that the BPAG1-n isoforms were not expressed in detectable quantities. The IFBD2 probe specifically labeled BPAG1-b mRNA in myocardium, skeletal muscle masses, vertebrae cartilage, and epithelia of the tongue (Fig. 4 B). More ubiquitous labeling patterns were observed with probes prepared for the ABD, plakin domain, SR-containing rod domain, and MTBD that would label BPAG1-a and BPAG1-b (Fig. 4 C and unpublished data). Strong signals were found with these probes in nervous tissues, especially at the pituitary primordium, the cranial ganglia, and the dorsal root ganglia (DRG). To determine the major form of BPAG1 expressed in the DRG, we hybridized a series of adjacent transverse sections with probes against various domains. Hybridization signals were obtained only with probes against the ABD, plakin domain, SR-containing rod domain, and MTBD, but not with the CC rod domain, IFBD1, and IFBD2 probes. These results demonstrated that BPAG1-e, BPAG1-n, and BPAG1-b are not expressed in high quantities in the DRG, and that the major form there is BPAG1-a (Fig. 4, D–F, and unpublished data).

Bottom Line: We have analyzed the BPAG1 locus in detail and found that it encodes different interaction domains that are combined in tissue-specific manners.BPAG1-a is composed of the ABD, the plakin domain, the SR-containing rod domain, and the MTBD.BPAG1-b is highly expressed in muscles, and has extra exons encoding a second IFBD between the plakin and SR-containing rod domains of BPAG1-a.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.

ABSTRACT
Bullous pemphigoid antigen 1 (BPAG1) is a member of the plakin family with cytoskeletal linker properties. Mutations in BPAG1 cause sensory neuron degeneration and skin fragility in mice. We have analyzed the BPAG1 locus in detail and found that it encodes different interaction domains that are combined in tissue-specific manners. These domains include an actin-binding domain (ABD), a plakin domain, a coiled coil (CC) rod domain, two different potential intermediate filament-binding domains (IFBDs), a spectrin repeat (SR)-containing rod domain, and a microtubule-binding domain (MTBD). There are at least three major forms of BPAG1: BPAG1-e (302 kD), BPAG1-a (615 kD), and BPAG1-b (834 kD). BPAG1-e has been described previously and consists of the plakin domain, the CC rod domain, and the first IFBD. It is the primary epidermal BPAG1 isoform, and its absence that is the likely cause of skin fragility in mutant mice. BPAG1-a is the major isoform in the nervous system and a homologue of the microtubule actin cross-linking factor, MACF. BPAG1-a is composed of the ABD, the plakin domain, the SR-containing rod domain, and the MTBD. The absence of BPAG1-a is the likely cause of sensory neurodegeneration in mutant mice. BPAG1-b is highly expressed in muscles, and has extra exons encoding a second IFBD between the plakin and SR-containing rod domains of BPAG1-a.

Show MeSH
Related in: MedlinePlus