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Human Molecular Genetics Pages 1299-1303
Reduced levels of dystrophin associated proteins in the brains of mice deficient for Dp71
Introduction
Results
Discussion
Materials And Methods
   Preparation of tissue extracts
   Sucrose gradient centrifugation
   Western blot analysis
   Antibodies
Acknowledgements
References

Reduced levels of dystrophin associated proteins in the brains of mice deficient for Dp71

Reduced levels of dystrophin associated proteins in the brains of mice deficient for Dp71 David S. Greenberg, Yechezkel Schatz, Zehava Levy, Paola Pizzo, David Yaffe and Uri Nudel*

Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel

Received April 22, 1996; Revised and Accepted June 6, 1996

Duchenne muscular dystrophy (DMD) is a progressive degenerative lethal muscle disease. A significant proportion of DMD affected children suffer also from mental retardation. The rod shaped protein, dystrophin, which is absent from or defective in the muscle of DMD patients, binds to a number of membrane associated proteins (known collectively as dystrophin associated proteins [DAPs]). The levels of DAPs is greatly reduced in the muscle of DMD patients and mdx mice, which lack dystrophin. In addition to dystrophin isoforms, the DMD gene codes also for several smaller proteins. One of the small proteins, Dp71, is expressed in most or all non-muscle tissues and is the major DMD gene product in the brain. The function of the small DMD gene products is unknown. Here we show that mutant mice which do not express the smaller non-muscle products of the DMD gene have a reduced level of DAPs in their brain. This suggests that Dp71 is important for the formation and/or stabilization of a DAPs complex in brain.

INTRODUCTION

The Duchenne muscular dystrophy (DMD) gene is an extremely large gene which is now known to code for a number of muscle and nonmuscle proteins. The product of the gene in muscle, dystrophin, is a 427 kDa rod shaped protein. The lack of dystrophin results in Duchenne muscular dystrophy, an X-linked recessive disease of extensive muscle wasting, early loss of mobility and early mortality (1 ,2 ). Approximately 30% of DMD patients exhibit mild to severe mental retardation.

Dystrophin consists of four domains; an N-terminal actin binding domain, a large domain of spectrin-like repeats, a cysteine rich and C-terminal domains (2 ). The N-terminal domain binds to cytoplasmic actin and the C-terminal region binds to a complex of sarcolemmal proteins and glycoproteins known collectively as the dystrophin associated proteins (DAPs) or dystrophin associated glycoproteins (DAGs) (3 -5 ). [alpha]-Dystroglycan, one of the components of the DAPs complex, is known to bind to muscle specific laminin (merosin), an important component of the extra cellular matrix (6 ), thus indicating one possible role for dystrophin as a part of a linkage between the intercellular cytoskeleton and the extracellular matrix. [alpha]-Dystroglycan has also been identified, as a receptor for agrin, a protein responsible for aggregation of the acetyl choline receptors at the neuromuscular junction (7 ,8 ). In DMD patients and mdx mice, which lack dystrophin, the levels of all the DAPs are significantly reduced. This reduction, which is not seen on the transcriptional level, is presumably due to a reduced stability of the DAPs complex when there is no dystrophin to anchor the complex (9 -11 ). Two of the proteins of the DAPs complex, [alpha]-dystroglycan and [beta]-dystroglycan, are also expressed in non-muscle tissues, though their role in those tissues is not known (12 ).

We have shown the existence of a 70.8 kDa DMD gene product called Dp71 (13 ,14 ) which is controlled by a promoter located between exon 62 and 63 of the DMD gene (15 -18 ). It contains the cysteine rich and C-terminal domains which in dystrophin have been shown to be involved in the interaction with the DAPs complex. It lacks the large spectrin-like repeats domain and the N-terminal actin-binding domain (13 ,14 ). Like dystrophin, it is associated with the cell membrane (19 ). Three other small products of the DMD gene have recently been characterized: Dp116, Dp140, Dp240, with molecular weights of 116 kDa, 140 kDa, and 240 kDa, respectively. Dp116 was detected only in peripheral nerve (20 ). Dp140 is expressed primarily in brain and kidney (21 ). Dp240 is found in the retina (22 ). All these products contain the cysteine rich and C-terminal domains and part of the spectrin-like repeat domain. The function of the smaller products of the DMD gene is not known.

It has previously been shown that ectopic expression of exogenous Dp71 in the muscle of mdx mice (which lack dystrophin) restored normal levels of the DAPs (though it did not prevent muscle degeneration). This suggested that Dp71 is capable of interacting with the DAPs complex (23 ,24 ). In order to examine directly whether the endogenous Dp71 in non-muscle tissues interacts with DAPs and plays a role in the formation of a DAPs complex in these tissues, we have examined the levels of the DAPs in the tissues of mutant mice which do not express Dp71. We show that the levels of DAPs in the brain of these mice is significantly reduced.

RESULTS

As shown in Figure 1 , Dp71 is expressed in a wide variety of tissues and is the major product of the DMD gene in most tissues including brain.


Figure 1. Distribution of Dp71 and dystrophin in rat tissues. Total rat tissue extracts were prepared and analyzed by western blotting as described in Materials and Methods. The blot was immunostained with monoclonal antibody MANDRA1.

Mdx mice contain a mutation in exon 23 of dystrophin, which abolishes dystrophin expression (25 ,26 ). Since this mutation is in the region encoding the N-terminal part of the spectrin-like repeats of dystrophin, it does not affect the expression of Dp71 and the other known small products of the gene. In contrast, mdx3CV(3CV) mice contain a splicing mutation in intron 64 of the DMD gene which leads to aberrant splicing and the early termination of both the dystrophins and Dp71 as well as other known products of the DMD gene (27 ). Although it has been reported that 5% of the transcripts undergo exon skipping and therefore are capable of giving rise to almost full length protein, we did not detect either Dp71 or dystrophin in these mice (Fig. 2 ). Heterozygous 3CV/+ female litter mates express both Dp71 and dystrophin, as expected (Fig. 2 ). In order to examine the levels of the DAPs in these mice, total tissue extracts or partially purified membrane fractions were prepared from a number of tissues of 3CV, mdx and normal littermate heterozygous mice. Western blots stained with a monoclonal antibody against [beta]-dystroglycan showed a significant decrease in the level of the protein in the brain of 3CV mice (Fig. 3 ) but not in the brain of mdx mice. The blots were also stained with a monoclonal antibody against [beta]-actin as a loading control. In muscle, which normally does not contain Dp71, [beta]-dystroglycan was reduced in both 3CV as well as mdx, as expected (Fig. 4 ). In a number of other tissues examined, including liver, (Fig. 4 ) as well as testis and kidney (data not shown) no significant difference in the level of the [beta]-dystroglycan between wild type, mdx and 3CV mice was observed.


Figure 2. Expression of Dp71 and dystrophin in mdx, mdx3CV and wild type mice. Preparation of total tissue extracts and western blot analysis are described in Materials and Methods. The blot was immunostained with monoclonal antibody MANDRA1. The band in the region of Dp71 seen in the muscle samples is not specific since it is also obtained in blots stained with the second antibody only.


Polyclonal antibodies against [alpha]-dystroglycan were used to examine the levels of the protein in the brain. Muscle [alpha]-dystroglycan migrates as an ~156 kDa protein but brain [alpha]-dystroglycan migrates as an ~120 kDa protein, probably due to tissue specific differences in glycosylation (7 ,12 ). As observed with [beta]-dystroglycan, a significant reduced level of [alpha]-dystroglycan was found in the brain of 3CV mice as compared to the brain of mdx and wild type mice (Fig. 5 ). Staining with a monoclonal antibody against [beta]-actin showed similar levels of actin in all samples.

In order to further analyze the interaction of Dp71 with the DAPs, the microsomal fractions of brain and liver were isolated, treated with 1% Triton *100 and run on a sucrose gradient. Samples from sequential fractions were run on an SDS polyacrylamide gel and immunostained for Dp71 and [beta]-dystroglycan. In the brain sample both Dp71 and [beta]-dystroglycan were found largely in the same fractions suggesting co-sedimentation of the proteins (Fig. 6 ) whereas in the liver sample, only a part of the Dp71 was found in the fractions containing [beta]-dystroglycan and most of the Dp71 exhibited a heavier distribution profile (Fig. 6 ). Interestingly, the distribution of utropin in the brain extract was similar to that in liver extracts (tubes 6-10 of the two gradients, not shown).

DISCUSSION

The DMD gene codes for several dystrophin isoforms and a number of smaller non-muscle proteins. Although at least some of the possible functions of dystrophin in muscle are known, nothing is known about the role of, and the interactions of, the non-muscle products of this gene. The role of Dp71 is of special interest since it is the major product of the DMD gene in all non- muscle tissues examined so far, and is the first product detected during early embryogenesis. The role of the dystroglycans in non-muscle tissues is also unknown though it has recently been shown that they may play a role in epithelium development in the kidney (28 ).

We have previously shown that ectopically expressed Dp71 in the muscle of mdx mice is capable of restoring normal levels of DAPs, thus suggesting interaction with the DAPs complex in this artificial muscle degeneration system. Using mutant strains of mice we show here that the absence of Dp71 in the brain is correlated with a reduced level of the DAPs. This result suggests that Dp71 plays a role in the function or organization of the dystroglycan complex in the brain. Consistent with this, it has been shown by in situ hybridization that Dp71 and dystroglycan mRNAs are found in the same regions of the brain (29 ).

Other 3' products of the DMD gene are also absent in 3CV mice but only Dp140 has been reported to be expressed in the brain (21 ). Dp71 is by far the predominant DMD gene product in the brain (Fig. 1 ) and it is reasonable to speculate that it is the absence of Dp71 which is the main reason for the reduction in the level of the dystroglycans in the brain of 3CV mice. It is, though, impossible at present to exclude the possibility that the absence of Dp140 also plays a role in the reduction in the levels of the DAPs in the brain of 3CV mice. In order to conclusively answer this question, mice in which the expression of Dp71 is specifically abolished would have to be analyzed.


Figure 3. The level of [beta]-dystroglycan is significantly reduced in the brain of mdx3CV mice.Total brain extracts of the indicated mice strains were analyzed by western blotting as described in Materials and Methods. The blots were stained with monoclonal antibody 43 DAG/8D5. As a loading control, one of the blots was also stained with anti [beta]-actin antibody. The wild type mice were littermate heterozygous mdx3CV/+ females.


Figure 4.The level of [beta]-dystroglycan is not reduced in the liver of mdx3CV mice.Total liver and muscle extracts of the indicated mouse strains were analyzed by western blotting. The blot was stained with the monoclonal antibody 43DAG/8D5.

Interestingly, in other non-muscle tissues examined in which Dp71 is normally expressed, there was no concordant reduction in the levels of [alpha] and [beta] -dystroglycans in mice lacking Dp71. Sucrose gradients analysis also suggest that there may be a specific interaction between Dp71 and the dystroglycans in the brain which is stronger than or different from the interaction in liver. However, since we were unable to coimmunoprecipitate Dp71 and [beta]-dystroglycan from brain extracts (not shown), it is likely that the interaction between these two proteins is relatively unstable.

The different behavior of the dystroglycans between brain and the other non-muscle tissues that were tested may indicate that either other proteins besides Dp71 and dystrophin are able to interact with the dystroglycan complex in tissues other than brain, or that the dystroglycans play a different role in these tissues and do not require a cytoplasmic anchor. Since not all DAPs which were identified in muscle are present in non muscle tissues (12 ), it is also possible that the composition of the DAP complex in the brain and its interaction with other proteins is different from that in other non-muscle tissues which have been examined.

Proteins which are not products of the DMD gene and may bind to the DAPs in non-muscle tissues, such as liver and testis, include utrophin which shares with dystrophin considerable sequence similarity in the regions that are involved in dystrophin in the association with the DAPs (30 ). Smaller products of the DRP gene have also been reported, though they have so far been found only in the brain (31 ). An 87 kDa protein has also been reported in Torpedo to associate with DAPs which also shares sequence similarity with the C-terminal region of dystrophin (32 ). There is a mammalian homologue to the 87 kDa protein. However it is not known whether either of these proteins is capable of binding to dystroglycan (33 ). The present investigation suggests that these proteins cannot replace Dp71 in the brain. The level of utropin is elevated in muscles of DMD patients and mdx mice. However, using western blots, we did not find a difference in the levels of utropin in the brain between mice expressing Dp71 and 3CV mice (not shown).

The role of the dystroglycan complex in brain is unknown. It may act as an extracellular matrix binding protein or it may act as a receptor for agrin-like molecules which may play a role in synaptogenesis. The role of Dp71 may be to stabilize or properly localize the complex in the membrane. Other as yet unidentified proteins may also interact with the Dp71-dystroglycans complex in a manner similar to the recently discovered interaction of nitric oxide synthesase (NOS) with dystrophin in the muscle (34 ).

All known DMD gene products share the highly conserved C-terminal and cysteine rich domains. These domains are also the most conserved regions between the DMD gene products and utrophin (34 ). It is possible that in addition to the potential role of the rod shaped dystrophin in creating a mechanical linkage between the DAPs complex and the cytoskeleton, these two C-terminal domains serve in a very wide range of tissues in additional, yet unknown, functions which may be associated with a DAPs-like complex.

Due to the locations of Dp71 promoter in the 3' region of the DMD gene, in most DMD patients the expression of Dp71 is unaffected. It is, therefore, clear that in many cases mental retardation is not related to the absence of Dp71. However, some investigators have found that mutations in the 3' region of the DMD gene, which result in the absence of both dystrophin and Dp71, are correlated with a much higher incidence of severe mental retardation than normally found in DMD (e.g. 35 ). The results reported here, indicating interactions between a DMD gene product and membrane associated proteins in the brain, may help shed some light on the function of non muscle products of the DMD gene as well as the cause of mental retardation in at least some of the patients with DMD.


Figure 5. The level of [alpha]-dystroglycan is significantly reduced in brain of mdx3CV mice. The level of [alpha]-dystroglycan in brain microsomal fractions from the indicated mice strain was analyzed by western blotting. The blots were stained with anti [alpha]-dystroglycan polyclonal antibody IIH6C4, and with an antibody again [beta]-actin, as loading control.


Figure 6. Sucrose density gradient centrifugation analysis of Dp71 and [beta]-dystroglycan complexes from mouse liver and brain. Microsomal fractions were prepared from mouse liver and brain, and membranes were solubilized in 1% Triton X-100. The protein complexes were fractionated on 10-25% sucrose gradients. Dp71 and [beta]-dystroglycan levels in the various fraction were analyzed by western blotting, as described in Materials and Methods. Numbering of fractions is from bottom to top. The pattern of sedimitatin shown in the figure was obtained in two independent experiments. We do not have an explanation for the band stained for Dp71 in fraction No. 10.

MATERIALS AND METHODS

Preparation of tissue extracts

For direct analysis by western blotting, rat tissue samples (400 mg) were homogenized (polytron homogenizer, 40 s at full speed) in 5 ml of electrophoresis sample buffer [67.5 mM Tris-HCl pH 6.8; 20% (v/v) glycerol, 15% SDS, 5% 2 mercaptoethanol, 0.001% bromophenol blue]. After heating for 20 min at 60oC, the samples were stored at -80oC.

Microsomal fractions were prepared from mouse brain and liver as follows: The tissue was cut to small pieces and homogenized by tight fitting Dounce homogenizer (20 strokes) in 10 vol of homogenization buffer containing 0.3 M sucrose (homogenization buffer: 10 mM Tricine pH 7.4, 1 mM EDTA, 1 mM PMSF, 0.1 mM paraminobenzoic acid, 1 mg/ml leupeptine, 1 mg/ml pepsatine). Nuclei and tissue debris were removed by 10 min centrifugation at 2000 g. The supernatant was spun at 20 000 g for 30 min, and the membrane pellet was dissolved in electrophoresis sample buffer.

Microsomal fractions that were further fractionated on sucrose gradients were prepared by a similar procedure with the following modifications. Homogenization was done in 4 volumes of homogenization buffer, the membrane pellet was dissolved in the homogenization buffer, insoluble material was removed by 5 min centrifugation at 5000 g, and Triton *100 was added to the supernatant at a final concentration of 1%.

Sucrose gradient centrifugation

One ml samples of Triton *100 treated microsomal fractions were loaded on 10-25% sucrose gradients (in homogenization buffer containing 1% Triton *100) and spun in a Beckman SW41 rotor at 34 000 r.p.m. for 18 h at 4oC. Fractions of 0.9 ml were collected starting at the bottom of the gradient.

Western blot analysis

Protein samples were size-fractionated on 3-10% polyacrylamide SDS gradient gels. Electrophoresis, blotting and immunostaining were done as previously described (23 ).

Antibodies

MANDRA1 is a monoclonal antibody which recognizes the C-terminal domain of human dystrophin (36 ). 43DAG/8D5 is a monoclonal antibody against [beta]-dystroglycan (37 ). Polyclonal antibody IIH6C4 against [alpha]-dystroglycan (156 DAG) was characterized previously (12 ). Anti-[beta] actin is a monoclonal antibody specific for beta actin (Sigma).

ACKNOWLEDGEMENTS

This work was supported by research grants from the Muscular Dystrophy Association of USA, the Muscular Dystrophy Group of Great Britain and Northern Ireland, the Association Francaise contre les Myopathies, Leo and Julia Forchheimer Center for Molecular Genetics at the Weizmann Institute of Science, the Israeli Academy of Sciences and the Minerva Foundation, Munich, Germany. U.N. is incumbent of the Eliass Sourasky Professorial Chair at the Weizmann Institute of Science. We thank Dr L. Anderson for the kind gift of the antibody 43DAG/8D5, Dr G.E. Morris for the antibody MANDRAl and Dr K. Campbell for the antibody IIH6C4, and Dr G. Bulfield for providing us with the founders for the mdx colony. The founders of the mdx3CV colony were a gift from the late Dr V.M. Chapman.

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*To whom correspondence should be addressed

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