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Keywords:

  • periostin;
  • OSF-2;
  • βig-H3;
  • fasciclin;
  • heart;
  • endocardial cushion;
  • valvulogenesis;
  • epithelial-mesenchymal transformation;
  • cell adhesion

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS AND DISCUSSION
  5. Acknowledgements
  6. LITERATURE CITED

Periostin, a member of the fasciclin gene family, acts as a cell adhesion molecule through binding to cell surface integrins. Periostin expression has previously been shown to increase substantially following transforming growth factor β (TGF-β) and bone morphogenetic protein stimulation. As these molecules are indispensable for cardiac development, we sought to clone the chicken ortholog of periostin and evaluate its spatiotemporal expression pattern during heart morphogenesis. We show by Northern analysis, whole mount and section in situ hybridization experiments that periostin is predominantly expressed in the developing endothelium of the ventricular trabeculae as well as in the endothelium and mesenchyme of the outflow tract and atrioventricular endocardial cushions. Cardiac expression continues into fetal development where periostin is seen predominantly in the valve leaflets and supporting chordae tendinae. © 2004 Wiley-Liss, Inc.

Periostin is a disulfide-linked 90 kDa cell adhesion protein originally cloned from a mouse osteoblast cell line (Takeshita et al., 1993). To date, the mouse, human, zebrafish, and rat periostin orthologs have been reported (Takeshita et al., 1993; Sasaki et al., 2001; Ito et al., 2002; Kudo et al., 2004). Periostin contains four repeated domains related to those found in the ancestral insect protein, fasciclin I. Functionally, periostin interacts with integrins to support cell adhesion and spreading of chondrocytes, fibroblasts, and a number of cancer cell lines (Gillan et al., 2002; Nakamoto et al., 2002; Bao et al., 2004; Shao et al., 2004). This interaction is accomplished through highly conserved stretches in the second and fourth fasciclin-like repeats, not through typical integrin-RGD binding motifs. In turn, through interactions with heparin as well as yet unidentified extracellular matrix proteins (Sugiura et al., 1995), periostin is also able to associate with the extracellular milieu.

Members of this gene family, including periostin and βig-H3 (TGF-β-induced gene clone 3), are coexpressed in a variety of specialized connective tissues during development. Most notably, murine periostin and βig-H3 are preferentially expressed in the periodontal ligament (PDL), the periosteum, as well as the endocardial cushions and valves of the developing heart (Horiuchi et al., 1999; Kruzynska-Frejtag et al., 2001; Ohno et al., 2002a, b; Doi et al., 2003; Ferguson et al., 2003; Wilde et al., 2003). The regulation of periostin expression in these cell types is not yet well understood. However, there is increasing data demonstrating that stress responses, as well as bone morphogenetic protein (BMP) and transforming growth factor β (TGF-β), stimulate periostin transcription (Horiuchi et al., 1999; Ji et al., 2000; Stanton et al., 2000; Wang et al., 2003; Wilde et al., 2003). For example, mechanical stress forces in the PDL, periosteum, and heart stimulate periostin expression. Similarly, during bone development, periostin is upregulated in part by BMP2/4. However, during osteoblast differentiation, expression decreases, suggesting that this protein may function as an antiosteogenic molecule. In the heart, TGF-β and BMP growth factors secreted by the myocardium stimulate endocardial cushion growth and development. These endocardial cushions play an essential role in valvuloseptal morphogenesis, a developmental process indispensable to the formation of a normal four-chambered heart (Markwald et al., 1977; Eisenberg and Markwald, 1995). Therefore, to investigate the role that periostin plays in valvuloseptal development, we report the cloning of the chicken periostin cDNA and an analysis of its embryonic and fetal cardiac expression.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS AND DISCUSSION
  5. Acknowledgements
  6. LITERATURE CITED

Cloning of Chicken Periostin and βig-H3

Stage 25 chicken heart RNA was isolated using Rneasy Columns (Qiagen) and reverse-transcribed into cDNA (Stratagene). Sequence data from a partial cDNA clone (GB AF31262) was used to design a 5′ oligo (5′-GCGACAGAGGACTAGAGATG-3′). A full-length periostin clone was obtained by PCR using the 5′ oligo and a 3′ linker primer incorporated into the cDNAs. Sequencing of both DNA strands of periostin was performed on an ABI sequence analyzer. An EST for βig-H3 corresponding to bases 450–3000 of GB AB005553 was obtained from University of Delaware, Delaware Biotechnology Institute.

Northern Analysis

Chicken RNA was isolated from a variety of stages (according to Hamburger and Hamilton) and tissue types (Qiagen). RNA from the craniofacial region was extracted primarily from the mandibular and maxillary processes. The RNA from the heart region was extracted from the entire heart tissue, including the outflow tract. Total RNA was electrophoresed on a 2% agarose/formaldehyde/1Xmops gel. The gel was blotted onto a nitrocellulose membrane, prehybridized and hybridized with radiolabeled probes according to standard protocol (NEN Life Science Products). The periostin probe used corresponds to the first 240 bp of the cDNA isolated. A 780 bp piece of the human GAPDH probe was used for normalizations. Hybridized membranes were washed and subjected to autoradiography for 4 hr. Densitometric analysis was performed using NIH Image.

Whole Mount and Section In Situ Experiments

Whole mount in situ was performed by generating sense and antisense periostin (first 240 bases) and βig-H3 (bases 1599–2069) RNA probes (riboprobes). Based on database sequence homology searches, the sequences for periostin and βig-H3 used in the in situ experiments are not anticipated to cross-react with other family members and are highly specific for either periostin or βig-H3, respectively. Riboprobes were generated by a DIG RNA labeling (SP6/T7) kit (Roche). Riboprobes were purified (Rneasy-Qiagen) and quantified by UV spectroscopy. Whole mount in situ hybridization and detection procedures were followed as previously described with slight modifications (Irving et al., 1996). In situ experiments on tissue sections were performed according to Moorman et al. (2001) using the same riboprobes described above. In situ experiments were carried out on embryos/embryonic hearts from stage 16 to day 12. Embryos were staged according to Hamburger and Hamilton (1951). Specific signal was only observed when sections or whole hearts were hybridized with the antisense riboprobe. No signal was detected when using the control sense riboprobe.

RESULTS AND DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS AND DISCUSSION
  5. Acknowledgements
  6. LITERATURE CITED

Chicken Periostin Cloning and Expression

cDNA clones for periostin were obtained using RT-PCR from a stage 25 chick heart cDNA library. The longest clone obtained was 2,655 bases in length (GB AY657005), which encodes a putative protein of 841 amino acids (Fig. 1) with a predicted molecular weight of approximately 90 kDa. This sequence contains an additional 30 amino acids in the carboxyl tail as compared to previously described rat, mouse, and human periostin proteins, suggesting a novel isoform in chickens. Overall, chick periostin shows high sequence homology at the amino acid level with other members of the periostin family (65%, 70%, and 73% identical to mouse, human, and rat, respectively). The chicken periostin protein consists of four fasciclin I-like repeats, each of which contain two highly conserved sequences (H1 and H2). Even though these sequences lack a typical RGD-integrin binding motif, they are still capable of interacting with a host of different integrins and thereby affecting cell adhesion properties (Gillan et al., 2002; Bao et al., 2004; Shao et al., 2004).

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Figure 1. Chicken periostin peptide sequence. Deduced peptide sequence of a full-length cDNA clone (not shown) encoding the 841 amino acid periostin protein. The putative signal sequence is underlined and italicized at the amino terminus. The four conserved fasciclin I-type repeats are indicated in bold. Within these domains, the H1 and H2 sequences are denoted. H1 stretches are italicized and underlined; H2 stretches are underlined.

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Northern analysis of periostin was performed on chicken RNA isolated from various stages beginning at stage 16 and ending at stage 29 (Fig. 2). In all samples examined, a single band representing periostin transcript(s) is evident at approximately 4.5 Kb. Initially, faint periostin expression is seen at stage 16 in whole embryo RNA preparations. Due to high levels of periostin expression reported in the murine heart and teeth (Kruzynska-Frejtag et al., 2001, 2004), we focused primarily on cardiac and craniofacial development. Commencing at stage 23, moderate levels of periostin are seen in the heart. Expression increases over time with peak levels around stage 29. A similar trend, albeit at significantly lower levels, was observed during craniofacial development. In order to elucidate a potential role for periostin during heart development, the precise spatiotemporal expression pattern was analyzed through whole mount and section in situ hybridization experiments.

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Figure 2. Northern blot analysis of chicken periostin transcripts during development. A Northern blot containing 20 μg/lane of total RNA from indicated embryonic time points and tissues was hybridized with a partial chicken periostin cDNA probe. One major transcript of 4.5 Kb was detected at all time intervals. Periostin was more highly expressed in tissues during cardiac development than craniofacial development. As development proceeds, periostin mRNA becomes more abundant in both tissues examined. GAPDH is used as a loading control.

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Periostin Expression in Embryonic Cardiac and Extracardiac Regions

Whole mount in situ experiments at stage 16 showed no expression of periostin in the heart (Fig. 3A). Cardiac expression of periostin was first detectable at stage 17 (Fig. 3B) in the endothelium of the right ventricle. By stage 18, periostin expression becomes more uniform throughout the trabeculated endothelium of both the right and left ventricles (Fig. 3C). At stage 18, periostin mRNA was also weakly expressed in the endocardial cushions of the outflow tract (OFT) but not in the atrioventricular (AV) cushions (Fig. 3C, arrowheads). In this report, the outflow tract is used to describe the vascular conduit between the embryonic right ventricular segment and the aortic arches. By stage 21, cardiac expression of periostin intensifies in the trabecular endothelium as well as in the OFT and AV cushions (Fig. 3D and E). At stage 25, abundant levels of periostin mRNA persist in the outflow tract and AV cushions as well as in the endothelium of the ventricular trabeculae (Fig. 3F). At stage 29, periostin expression is maintained in the endothelial lining of the trabeculae and becomes intensely expressed in the truncus or distal component of the outflow tract (Fig. 3G).

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Figure 3. Whole mount in situ hybridization of chicken periostin during cardiogenesis from HH stages 16–29. A: Periostin mRNA is not detectable at stage 16 in the heart. B: Expression commences at stage 17 and becomes more abundant by stage 18 (C) in the endothelial lining of the ventricular trabeculae (40× magnification). C: Expression within the OFT cushion expansions begins at stage 18 (arrowheads). D and E: Periostin transcription is maintained within the trabecular endothelium and increases in the OFT cushions at stage 21 (arrow in D). At this time point, the superior and inferior atrioventricular cushions (arrowheads) begin expressing periostin mRNA (40× magnification). F: By stage 25, the trabecular endothelium of the right ventricle shows more abundant periostin transcripts. The OFT (arrowhead) and AV cushions (arrow) express abundant amounts of periostin mRNA (20× magnification). G: At stage 29, whole mount in situ shows abundant periostin expression in the distal portion of the outflow tract (truncus) as well as in the trabecular endothelium (20× magnification). RV, right ventricle; LV, left ventricle; At, atrium; AVC, atrioventricular canal; IAVC, inferior AV cushion; SAVC, superior AV cushion; Co, conus; Tr, truncus.

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Section in situ data at stage 25 showed abundant periostin mRNA in the endocardial layer of the OFT and AV cushions (Fig. 4A). In both the OFT and AV cushions, a marked gradient of expression from endothelium to myocardium was observed. A subset of mesenchymal cells immediately adjacent/underlying the endothelium of the OFT cushions was positive for periostin. Similarly, the mesenchyme underlying the endothelium of the AV cushions showed the highest levels of periostin expression (Fig. 4A). Weak or no detectable expression of periostin was seen in cells further away from the endothelium. No periostin expression was detectable in the myocardial layer underlying the mesenchymal cushion cells. This myocardium has been shown to secrete growth factors (BMP2/4 and TGF-βs) that induce an endocardial-mesenchymal transformation (Nakajima et al., 1994; Eisenberg and Markwald, 1995; Markwald et al., 1996; Ramsdell and Markwald, 1997). These growth factors have been shown to induce periostin expression in in vitro experiments (Horiuchi et al., 1999; Ji et al., 2000; Stanton et al., 2000; Wang et al., 2003). Therefore, periostin may act as a signal sensor molecule that is associated with endocardial cushion growth and development.

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Figure 4. Section in situ hybridization of chicken periostin during cardiogenesis. A: In situ hybridizations of transverse sections at stage 25 demonstrate that periostin is expressed within the endothelium of the trabeculated myocardium (arrowheads). Also, periostin mRNA is abundant in the endothelium (EC) of the OFT and AV cushions (400× magnification). Expression is detected in a subset of mesenchymal cells underlying the endothelium of the cushions (arrowheads). B and D: In situ data of transverse sections at stage 29 show periostin mRNA restricted mainly to the mesenchyme and differentiating smooth muscle cells of the aortic arches (third and fourth arches shown). (D) High magnification of the aortic arches. Faint expression is seen in the condensed mesenchyme of the pulmonary artery and in the endothelium (arrowhead; 400× magnification). C: High magnification of the pulmonary artery. E: In situ hybridizations were performed on transverse sections through a stage 29 heart using an antisense riboprobe generated for βig-H3 (400× magnification). F: High magnification of the pulmonary artery. Expression is restricted primarily to the mesenchyme of the pulmonary outlet at the valve level and is most intense immediately adjacent to the myocardium (arrow). This expression is nonoverlapping and complementary to periostin expression, which is expressed in the distal valve leaflets (400× magnification). EC, endothelial cells; AA3 and AA4, aortic arch arteries 3 and 4; PA, pulmonary artery; LV, left ventricle.

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Section in situ data at stage 29 demonstrate that periostin expression is regionalized in the forming arterial tree, being prominent in the mesenchyme and differentiating smooth muscle cells of the aortic arches (Fig. 4B and D). The pulmonary artery, at the level of the forming pulmonary valve, shows weak expression in the endothelium and underlying condensed mesenchyme (Fig. 4B and C).

Based on the similarity in structure and proposed function of periostin and βig-H3, in situ experiments were performed for βig-H3 on stage 29 sections and compared to the data obtained for periostin (Fig. 4E and F). Unlike periostin, βig-H3 expression was not detected in the cells of the aortic arch arteries. βig-H3 mRNA expression was instead highly restricted to the mesenchymal cells of the pulmonary outlet at the level of the forming pulmonary valve, being most abundant immediately adjacent to the myocardium (Fig. 4E and F). Therefore, at stage 29 at the level of the pulmonary valve, periostin expression is restricted primarily to the apical endothelium and adjacent mesenchyme, whereas the highest levels of βig-H3 expression is restricted to the peripheral aspects of the valve, being subadjacent to the myocardium. This unique complementary and nonoverlapping expression pattern within the valves as well as within the arterial tree may help define the boundaries of the aortic and pulmonary outlets versus the more distal arterial branches.

Periostin Expression in Valvulogenesis

During embryonic development, endocardial cushions undergo an inductive process resulting in the formation of the valve leaflets and their supporting suspensory apparatus (Nakajima et al., 1997; van den Hoff et al., 1999; Schroeder et al., 2003). Increasing evidence suggests that the valvular structures are derived primarily from the endocardial cells of the developing cushions (Lincoln et al., 2004). Data presented here demonstrate that periostin is intensely expressed in the endocardium of the cushions, suggesting that expression may be maintained in the valve structures. By embryonic day 12, the valve leaflets and supporting structures have matured and been remodeled. At this time point, cardiac expression of periostin mRNA was evaluated by whole mount and section in situ hybridization experiments. Abundant periostin message was detected in the chordae tendinae of the left ventricular AV junction, the semilunar valve leaflets of the aortic and pulmonary outlet segments, and the annulus fibrosae (Fig. 5). Periostin mRNA was detected in the mitral valve but not in the tricuspid valve. Within the mitral valve, expression was further restricted to the ventricular side of the leaflets. The lack of periostin expression in the tricuspid valve is different in chick than has been observed previously in mouse. In mouse, periostin mRNA is abundant in the tricuspid and mitral valves at E17 (Kruzynska-Frejtag et al., 2001). However, the tricuspid valve in chicken development is unique to avians since it is MF20/Nkx2.5-positive and consists almost entirely of muscle (Lincoln et al., 2004).

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Figure 5. Fetal cardiac expression of periostin. AD: Whole mount in situ hybridization of embryonic day 12 hearts (20× magnification). Prior to in situ analysis, the hearts were bisected (A, sagittal; B–D, frontal). Periostin mRNA expression is abundant in the chordae tendinae supporting the mitral valve leaflet of the day 12 heart (white arrow heads). Periostin is also expressed in the future annulus fibrosae region (black arrow head) and the semilunar valves (arrows). Notice that there is no detectable expression in the muscularized tricuspid valve (D, asterisk). E: Section in situ hybridization of a day 12 fetal heart showing periostin expression in the mitral valve leaflet (arrow). F: Sense control showing no positive staining. G: Magnification (400×) showing punctate periostin expression in the myocardium. H: Magnification (400×) of sense control showing no staining. RV, right ventricle; LV, left ventricle; LA, left atrium; Ao, aorta; PA, pulmonary artery; MV, mitral valve; IVS, interventricular septum.

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Additionally, punctate periostin mRNA expression was detected throughout the myocardium of the atria and ventricles (Fig. 5G). The function of periostin in the myocardium is not known, but may play a structural role in stabilizing the heart. This would indeed substantiate a potential role that periostin may play in remodeling the adult ventricle following stress responses, as has been reported in cases of myocardial infarction and hypertrophy (Stanton et al., 2000; Wang et al., 2003).

In conclusion, chicken periostin is expressed in a temporospatial pattern during cardiac development. The highest levels of periostin mRNA are detected in the embryonic trabecular endothelium and endocardial cushions, as well as the valvular structures of the fetal heart. To date, the role that periostin and other fasciclin I domain containing proteins play in valvulogenesis is not known. However, βig-H3 and periostin are able to function as antiosteogenic/chondrogenic molecules during development (Ohno et al., 2002a; Saito et al., 2002). Molecular markers of chondrogenesis and tendon development (type II collagen, scleraxis, tenascin, BMP, and TBX20) are present in the mature valve leaflets and supporting structures in the chick and mouse. Therefore, in order to maintain a normal phenotype, Periostin, βigH3, and possibly other fasciclin family members may define a novel gene family essential in maintaining proper nonosteo/chondrogenic valvular structures. The identification of the cellular origins and molecular pathways involved in valvulogenesis will undoubtedly provide important information on the etiology of congenital valve malformations as well as valvular calcification disease.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS AND DISCUSSION
  5. Acknowledgements
  6. LITERATURE CITED

Supported by National Heart, Lung, and Blood Institute/National Institutes of Health grants RO1-HL66231 (to C.H.M.) and RO1-HL33756 and Po1-HL52813 (to R.R.M. and A.W.).

LITERATURE CITED

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS AND DISCUSSION
  5. Acknowledgements
  6. LITERATURE CITED
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