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Article |
Address correspondence to Francesco Ramirez, Laboratory of Genetics and Organogenesis, Hospital for Special Surgery at the Weill College of Medicine of Cornell University, 535 East 70th St., New York, NY 10021. Tel.: (212) 7874-7554. Fax: (212) 774-7864. email: ramirezf{at}hss.edu
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Abstract |
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Key Words: achalasia; basement membrane; collagen; muscle transdifferentiation; nitrergic neurotransmission
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Introduction |
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Collagen XIX is the latest example of a nonfibrillar collagen type that localizes to BM zones and that may potentially have an anatomically restricted function. Collagen XIX is deposited at extremely low amounts (106% of dry tissue weight) in the BM zones of vascular, neural, and mesenchymal tissues (Myers et al., 1997). Collagen XIX forms higher order aggregates that may conceivably modulate cellmatrix interactions, cellcell communications, and/or local concentrations of signaling molecules (Myers et al., 2003). Embryonic expression of the collagen XIX (Col19a1) gene is transient and confined almost exclusively to differentiating muscles (Sumiyoshi et al., 2001). Onset of Col19a1 expression in myotomes and myotome derivatives occurs soon after activation of the myogenic regulatory factor (MRF) gene Myf5, and declines concomitantly to the accumulation of myogenin transcripts (Sumiyoshi et al., 2001).
The above findings are consistent with the notion that collagen XIX may be involved in muscle differentiation and function (Sumiyoshi et al., 2001). Unfortunately, experimental validation of this postulate has been hampered by the paucity of collagen XIX in tissues. Therefore, the present work was undertaken to overcome this problem using genetic means. Toward this end, we created a null mutation (N19) and a structural mutation (19) of the
1(XIX) collagen chain by targeting different regions of the Col19a1 gene in mouse embryonic stem (ES) cells. Characterization of the resulting mouse phenotypes demonstrated that collagen XIX plays a dual role in muscle physiology and differentiation. Specifically, we found that proper assembly of the collagen XIXrich BM zone is a prerequisite for nitric oxide (NO)dependent relaxation of the lower esophageal sphincter (LES) muscle, and that collagen XIX deposition into the matrix of the developing esophagus is an extrinsic determinant of skeletal myogenesis in this organ.
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Results |
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The structural mutation (19) was created by inserting the PGK-neo cassette in place of exons 3840 (Fig. 1 A, right). Exons 3840 code for the 20-residue NC3 interruption of the helical domain and for one and six collagenous tripeptides located amino- and carboxyl-terminal of it, respectively (Sumiyoshi et al., 1997). Chimeric animals were generated from two independently derived clones and the progeny was genotyped by Southern blot analysis using a diagnostic restriction enzyme cleavage site (Fig. 1 E). The deletion of exons 3940 maintains the frame of the Col19a1 transcript, and thus it is predicted to yield an internally deleted
1(XIX) chain that should participate in homotrimer formation. Sequencing of RT-PCRamplified products confirmed that the mutant transcript is in frame (unpublished data), whereas immunoblots identified a collagenase-sensitive product in the mutant tissue slightly smaller than the wild-type 165-kD species (Fig. 1 D). Finally, PCR amplification estimated that the mutant and wild-type Col19a1 alleles are expressed at comparable levels in the heterozygous
19 mouse (Fig. 1 F). Therefore, the
19 allele represents a structural mutation that eliminates one of the flexible points in the triple helix. Characterization of the two collagen XIX mutations initially focused on the more severe phenotype of the nullizygous mouse.
Collagen XIX null mice display altered esophageal morphology
Heterozygous N19 mice were born at the expected Mendelian frequency; they were morphologically normal, viable, and fertile. Homozygous N19 mice were born at the expected frequency as well, but the vast majority of them (95%) died within the first 3 wk of postnatal life, showing signs of malnourishment. Postmortem inspection of newborn homozygous mutants did not detect gross anatomical abnormalities, except for the smaller size of the internal organs. On the other hand, necroscopy of the few Col19a1/ mice that survived past weaning stage revealed a dilated esophagus (megaesophagus) with retention of ingesta, immediately above the diaphragm level (Fig. 2 A). Based on these observations, we reevaluated the pattern of Col19a1 expression in the embryonic digestive system, and found it to coincide with the formation and growth of the gastroesophageal junction. Specifically, in situ hybridizations revealed high Col19a1 expression in the lower-third portion of the embryonic esophagus destined to become the abdominal segment; thereafter Col19a1 activity becomes gradually restricted to the mature LES, while decreasing in the muscle layer of the proximal stomach (Fig. 2 B).
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Mechanical responses to nonadrenergic noncholinergic (NANC) nerve stimulation with EFS of sphincteric muscle strips from wild-type and nullizygous adult mice were measured in the absence and in the presence of L-NA, an inhibitor of NO synthase (NOS; Mashimo et al., 1996). As expected, we found that EFS elicited frequency-dependent relaxation of wild-type LES strips followed by pronounced rebound contraction, and that muscle relaxation was significantly reduced by L-NA treatment (Fig. 3, A and B). In marked contrast, mutant muscle strips failed to produce significant relaxation in response to EFS; furthermore, L-NA virtually eliminated any residual relaxation (Fig. 3, A and B). Comparable results were obtained in intact animals. Intraluminal pressure recorded at the LES level of adult Col19a1 null mice in fact showed significantly higher basal tone (three- to eightfold) than wild-type animals (Fig. 4 A). It also documented severely impaired or absent relaxation upon swallowing; even when present, relaxation was abnormally brief (Fig. 4 A). The results of the manometric tests were remarkably similar to those reported for achalasic patients (Richter, 2001). Altogether, the in vitro and in vivo experiments indicated that NO-dependent neurotransmission is perturbed in the collagen XIXdeficient LES.
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Immunostaining of collagen XIXdeficient LES tissue with antibodies against nidogen-1 documented a largely preserved BM, which, however, stained more intensively than the wild-type counterpart (Fig. 6 A). Electron microscopy confirmed this result by showing a thicker BM around the mutant SMC (Fig. 6 B). It also revealed that intercellular spacing of the mutant smooth muscle is appreciably greater than the wild-type control (Fig. 6 C). Additional abnormalities include convoluted SMC profiles, excessive extracellular accumulation of collagen fibrils, and highly irregular intercellular space (Fig. 6 C). Consistent with progressive degeneration of matrix organization, these morphological abnormalities were more pronounced in adult than newborn mutant mice (Fig. 6 C). Collectively, these analyses suggested a specialized and highly restricted role of collagen XIX in organizing the BM zone of the LES.
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Progression of muscle transdifferentiation in the wild-type 129/Sv mouse was monitored by following the expression of myogenin, an MRF that instructs skeletal muscle differentiation (Molkentin and Olson, 1996). In situ hybridizations at different prenatal and postnatal stages of esophageal development revealed that the front of myogenin expression reaches diaphragm level at birth, and gradually progresses into the abdominal segment of the esophagus during the first week of postnatal life (Fig. 7 A). The same analysis documented that the postnatal front of myogenin expression in the collagen XIXdeficient esophagus remains at the same level as at birth (Fig. 7 B). Immunostaining of the wild-type and mutant specimens for skeletal and smooth musclespecific proteins demonstrated that loss of MRF gene expression translates into failed muscle transdifferentiation in the entire abdominal segment of the Col19a1/ esophagus (Fig. 7 C). These results conclusively established a causal relationship between extracellular deposition of collagen XIX and developmentally programmed activation of MRF-driven smooth muscle transdifferentiation.
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Immunohistological examination of gastroesophageal tissues from four adult 19/+ mice and four
19/
19 littermates revealed normal transdifferentiation of the muscle layer in the abdominal segment of the esophagus (Fig. 6 B). By contrast, the EFS assay documented reduced or absent relaxation of LES muscle strips in half of the eight heterozygous and eight homozygous
19 specimens examined (Fig. 3 C). Moreover, LES samples from randomly chosen
19/+ or
19/
19 mice often displayed altered nidogen-1 immunostaining (unpublished data). Therefore, we concluded that the structural and compositional integrity of the BM zone are both prerequisites for proper LES function, and that only the latter is required for the developmentally regulated process of skeletal myogenesis.
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Discussion |
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Structural role of collagen XIX in LES physiology
Activation of inhibitory NANC nerves is critical for LES relaxation upon swallowing (Goyal and Hirano, 1996). Although NO is widely recognized as the major inhibitory neurotransmitter of NANC nerves, the mechanism and factors responsible for conveying NO signals to SMC remain ill-defined. Conflicting models postulate that the highly labile NO either diffuses freely in the extracellular space between nerve varicosities and SMC or is transduced to the target muscle cells by ICC-IM (Ward et al., 1998; Sivarao et al., 2001). The achalasia-like manifestations of mice lacking collagen XIX or producing structurally abnormal collagen XIX trimers imply that NO-dependent smooth muscle relaxation requires a properly organized LES matrix as well. That LES muscle relaxation is impaired in spite of a seemingly normal complement of ICC-IM and nitrergic nerves and of functionally viable SMC further supports this conclusion.
The hypertensive and nonrelaxing LES of the Col19a1 mutant mice resembles the clinical manifestations of human patients with achalasia (Goyal, 2001; Richter, 2001). The etiology of this primary esophageal motor disorder is heterogeneous and may include genetic, infectious, autoimmune, and degenerative factors. Loss of nitrergic nerves in achalasia is widely believed to cause hypertensive LES due to unopposed cholinergic excitation, a notion indirectly supported by the basal LES hypertension in nNOS/ mice (Goyal, 2001; Richter, 2001; Sivarao et al., 2001). Similarly, impaired LES relaxation to swallowing in nNOS/ mice underscores the prominent contribution of nitrergic neurotransmission to inhibitory neurotransmission (Sivarao et al., 2001). The manometric data from Col19a1/ and nNOS/ mice are virtually identical and as such, they emphasize functional equivalency between NO release from nitrergic varicosities and ECM organization. By contrast, c-Kit mutant (W/Wv ) mice, which lack ICC-IM, have a hypotensive LES with normal NANC relaxation (Sivarao et al., 2001). Hence, the data from the Col19a1 and nNOS null mice concur in strongly suggesting that ICC-IM play a lesser role than previously suggested in sphincteric muscle relaxation.
The structural role of the collagen XIXrich BM zone may extend beyond supporting NO-dependent relaxation of the LES to organizing the neuromuscular junction of the sphincteric muscle. In this respect, an analogy could be drawn with perlecan in clustering acetylcholinesterase to the synaptic basal lamina of the neuromuscular junction (Arikawa-Hirasawa et al., 2002). Our postulate is based on the intriguing observation that the NOS inhibitor L-NA affects the relaxation of mutant muscles relatively less than wild-type muscles (Fig. 3). Irrespective of the underlying mechanism, our work conclusively proves that collagen XIX is a new contributing factor to sphincteric muscle physiology.
Instructive role of collagen XIX in esophageal development
Collagenous and elastic macroaggregates have been traditionally viewed as the main structural determinants of connective tissue architecture. However, there is emerging evidence that they also participate in modulating a variety of cellular activities and signaling events (Ortega and Werb, 2002; Ramirez and Rifkin, 2003). For example, proteolytic products of collagens XV and XVIIIalso known as restin and endostatinhave been reported to control programs as diverse as angiogenesis, neuronal cell migration, and epithelial cell morphogenesis (O'Reilly et al., 1997; Sasaki et al., 1998; Ackley et al., 2001; Karihaloo et al., 2001). Moreover, failed regression of hyaloid vessels in the eyes of collagen XVIII-deficient mice has been interpreted to imply that this BM-stabilizing molecule promotes programmed cell death and macrophage activation during tissue remodeling (Fukai et al., 2002). Failed muscle transdifferentiation in Col19a1/ mice similarly implicates this collagen type in modulating a specific morphogenetic process.
Developmentally programmed cell transdifferentiation is a rare phenomenon in vertebrates that has been described for a few contractile cell types, including the mouse esophagus and the chick iris (Volpe et al., 1993; Patapoutian et al., 1995; Link and Nishi, 1998a; Kablar et al., 2000). Transdifferentiation in both organ systems involves the conversion of smooth muscle to skeletal muscle. Co-culture experiments have suggested that activin and follistatin coordinate muscle transdifferentiation in the chick iris (Link and Nishi, 1998b). That normal development of striated muscles and nicotinic receptor clusters take place in Mash1/ mice, which lack enteric neurons, has indicated that skeletal myogenesis in the mouse esophagus occurs independently of innervation (Sang et al., 1999).
The biological mechanism responsible for skeletal myogenesis in the mature muscle layer of the mouse esophagus is controversial. In the original description of the phenomenon, Patapoutian et al. (1995) reported that smooth-to-skeletal muscle conversion is preceded by MyoD and myogenin expression. Kablar et al. (2000) subsequently used transgenic and knock-in mice to document that initiation and progression of muscle transdifferentiation depend on Myf5 expression. The apparent discrepancy between these two reports may reflect the fact that each followed muscle transdifferentiation in different esophageal segments (i.e., abdominal vs. thoracic/cervical). Others have argued that smooth and skeletal muscles originate from distinct precursor cells already present at early embryonic stages (Zhao and Dhoot, 2000a,b; Rishniw et al., 2003). However, this argument is not supported by evidence of significant SMC apoptosis during esophageal development (Patapoutian et al., 1995; Kablar et al., 2000).
Our findings implicate the collagen XIXrich matrix as the first extrinsic factor to guide skeletal myogenesis in the developing mouse esophagus. Interestingly, the same morphogenetic defect was not observed in the C57/Bl/6J genetic background, implying that collagen XIX action is modulated by modifier gene products. On the other hand, association of an achalasia-like phenotype with the same physiological and morphological manifestations in both C57/Bl/6J and 129T2/SvEmsJ mutant mice indicated that distinct mechanisms are responsible for the genesis of LES dysfunction and failed muscle transdifferentiation. Along these lines, normal esophageal muscle transdifferentiation in mice producing abnormal collagen XIX trimers demonstrated that a specific peptide sequence (rather than the whole molecule) is involved in muscle transdifferentiation. One attractive mechanism is that the collagen XIXrich matrix may control the distribution and/or activity of growth factors that ultimately trigger MRF gene expression in the abdominal esophagus. The elegant work of Myers et al. (2003) supports this hypothesis. These investigators have shown that collagen XIX forms higher order aggregates in which individual molecules extend radially from a globular core of interacting NC6 domains. Therefore, they have argued that this configuration, together with the NC6 heparin-binding site, may contribute to localize and concentrate signaling molecules within the BM zone. Such a model is analogous to the recently reported involvement of extracellular microfibrils in limb patterning and lung morphogenesis through the modulation of TGFß/BMP signaling (Arteaga-Solis et al., 2001; Neptune et al., 2003). Alternatively, the flexibility of the collagen XIX monomers and the presence of a Tsp-N module in NC6 may regulate skeletal myogenesis by mediating critical cellmatrix and/or cellcell interactions (Myers et al., 2003).
Although the precise mechanism underlying the role of collagen XIX in muscle transdifferentiation remains undetermined, our work has yielded a number of interesting observations and plausible predictions. First, impaired muscle transdifferentiation is only seen in the absence of collagen XIX deposition and is associated with failed myogenin activation. This finding could be interpreted to indicate that collagen XIX lies upstream of the MRF(s) driving this morphogenetic pathway. Second, early embryonic expression of Col19a1 is in the region that will eventually become the abdominal segment of the adult esophagus, and that fails to transdifferentiate in collagen XIX null mice. Therefore, it is plausible to argue that SMCs become fated for cell conversion soon after onset of Col19a1 expression in the lower-third portion of the primitive esophagus. Third, persistency of the smooth muscle phenotype in null mice is confined to the abdominal segment and conversely, Col19a1 gene activity is absent in the upper two thirds of the wild-type esophagus. A likely explanation of these observations is that distinct factors and different mechanisms drive muscle transdifferentiation along the esophageal axis. Implicitly, this last prediction may reconcile the controversy about the identity of the MRF(s) driving esophageal transdifferentiation (Patapoutian et al., 1995; Kablar et al., 2000). The availability of the Col19a1 null mouse provides the opportunity to test these predictions and further characterize this poorly understood biological phenomenon.
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Materials and methods |
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Immunoblot analysis
Crude collagen XIX fraction was extracted from adult brains of wild-type and mutant mice as described previously (Sumiyoshi et al., 1997). The final 5 M NaCl precipitate was resuspended in 50 mM Tris-HCl, pH 7.5, 100 mM NaCl, and 0.5% NP-40; 100 µg of the crude collagen XIX preparation was then separated on 4.5% SDS-PAGE and electroblotted onto a PVDF membrane in the presence of 15 mM sodium-borate buffer. Immunoblots were probed with rabbit pAbs raised against a recombinant fusion protein produced by the pMAL-c2 expression plasmid (New England Biolabs, Inc.) and containing the sequence encoding aa 10041036 of collagen XIX. Immunocomplexes were detected using the ECL blotting system (Amersham Biosciences) with secondary goat antirabbit IgG conjugated with HRP (Santa Cruz Biotechnology, Inc.). For collagenase digestion, 7.5 U bacterial collagenase type III (Advance Biofactures) was added to 100 µg of crude collagen XIX extract, and was incubated for 2 h at 37°C in 50 mM Tris-HCl, pH 7.2, and 20 mM CaCl2.
Immunohistochemistry, electron microscopy, and in situ hybridizations
Esophagi were removed along with the LES from necropsied animals, fixed in 4% PFA, embedded in paraffin, serially sectioned, and immunostained with alkaline phosphatase conjugated to mAbs against smooth muscle actin or skeletal fast myosin (Sigma-Aldrich). Rabbit pAbs against nidogen-1 were provided by Dr. Ulrike Mayer (University of Manchester, Manchester, UK; Fox et al., 1991). For immunofluorescence staining, frozen LES sections were incubated overnight at 4°C with rabbit anti-nNOS antibody (1:500; BD Biosciences) and goat anti-cKit antibody (1:500; Santa Cruz Biotechnology, Inc.). After removal of unbound antibodies, sections were incubated with FITC-conjugated donkey antirabbit IgG and Texas redconjugated donkey antigoat IgG (1:200; Jackson ImmunoResearch Laboratories) for 2 h at RT. Slides were examined using a confocal laser scanning microscope (TCS-SP (UV); Leica) equipped with a four-channel spectrophotometer scan head and four lasers (Ar-UV, Argon, Krypton, and HeNe). Sections were illuminated simultaneously with the = 488- and
= 568-nm laser lines and the AOTF was adjusted such that no signal "cross-talk" occurred between channels. Gastroesophageal junctions were collected from 4-mo-old animals, fixed overnight in 4% PFA, processed through paraffin, and sectioned at 57-µm thickness. Sections were deparaffinized and treated with 100 µg/ml protease XXIV (P8038; Sigma-Aldrich) for 10 min at 37°C (Willem et al., 2002). Antibodies against nidogen-1 (1:1,000) were applied for 2 h at RT in a humid chamber; the streptavidin-HRP technique (LSAB 2 system; DakoCytomation) was used to localize the antibody and hematoxylin was used as a counterstain. Samples of the same tissues used for immunohistochemistry were processed for electron microscopy by fixation in 2% PFA plus 0.5% glutaraldehyde in 0.05 M cacodylate buffer, pH 7.2, for 4 h at 4°C. Tissues were rinsed, post-fixed for 1 h in 2% osmium tetroxide at RT, dehydrated, and embedded in Epon 812. Thin sections were stained with uranyl acetate for 20 min and with lead citrate for 5 min. Photographs were taken on a transmission electron microscope (CM-12; Philips) at 80 kV or using a transmission electron microscope (H-7000; Hitachi) operated at 75 kV. Confocal and electron microscopy were performed at the Mount Sinai Microscopy Shared Resource Facility (New York, NY) and at the Hospital for Special Surgery Analytical Microscopy Core Facility (New York, NY). In situ hybridizations were performed on serial tissue sections using Col19a1 and myogenin probes as described previously (Sumiyoshi et al., 2001).
Physiological tests
Mechanical responses of LES strips to EFS were measured using standard organ bath techniques in the presence or absence of 1 mM N-nitro-L arginine (L-NA; Mashimo et al., 1996). LES tone was also measured in the presence of increasing concentrations of bethanechol (0.1300 µM) followed by sodium nitroprusside (0.1100 µM) as described previously (Chakder et al., 1997). Intraluminal esophageal manometry was performed as described by Sivarao et al. (2001) using a custom-designed catheter assembly (Dentsleeve; Dentsleeve Pty Ltd.) that consists of silicon tubing made of three individual channels of a 0.3-mm inside and 0.6-mm outside diameter each. Swallows were induced by instilling a 1020-µl bolus of water on the tongue of the animals. To determine the integrity of the sphincteric muscle, isoprotenerol hydrochloride (0.4 µg/Kg) was injected i.v.
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Acknowledgments |
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This work was supported by grants from the National Institutes of Health (AR-38648, CA-095823, and DK-35385), the St. Giles Foundation, and the Japanese Ministry of Education, Science and Culture (Grant-in-aid for Scientific Research 11470312 and 11877275). The authors declare they have no competing financial interests.
This work is dedicated to the memory of Rupert Timpl.
Submitted: 9 February 2004
Accepted: 22 June 2004
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