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Endocrinology Vol. 144, No. 8 3618-3624
Copyright © 2003 by The Endocrine Society

Expression of Classical Cadherins in Thyroid Development: Maintenance of an Epithelial Phenotype throughout Organogenesis

H. Fagman, M. Grände, J. Edsbagge, H. Semb and M. Nilsson

Institute of Anatomy and Cell Biology (H.F., M.G., M.N.) and Department of Medical Biochemistry (J.E., H.S.), Goteborg University, SE-40530 Goteborg, Sweden

Address all correspondence and requests for reprints to: Dr. Henrik Fagman, Institute of Anatomy and Cell Biology, Goteborg University, Box 420, SE-40530 Goteborg, Sweden. E-mail: henrik.fagman{at}anatcell.gu.se.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The long distance between the final location of the thyroid gland in front of the trachea and the site of embryological specification at the tongue base suggests that active migration of the thyroid progenitor cells is required. During embryogenesis, similar morphogenetic events often involve epithelial to mesenchymal transition (EMT), which promotes the acquisition of a migrating phenotype. EMT is characterized by an altered expression of cadherin cell adhesion molecules, most notably loss of E-cadherin. To investigate whether a similar mechanism operates in thyroid development, we studied the expression of classical cadherins in the thyroid primordium of mouse embryos by immunohistochemistry. E-Cadherin was expressed at high levels in thyroid cells at all developmental stages. In contrast, R-cadherin expression was induced in the embryonic thyroid coinciding with the onset of folliculogenesis and was maintained in the adult thyroid along with E-cadherin. N-Cadherin, often associated with increased migrating capacity, was not detected in the thyroid primordium, but was expressed in the surrounding mesenchyme. These findings indicate that the epithelial phenotype is maintained in thyroid progenitor cells throughout organogenesis and favor the idea that translocation of the developing thyroid does not involve active migration of individual cells, but rather is secondary to movements of surrounding tissues.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE THYROID GLAND develops from the floor of the primitive pharynx and can first be distinguished in the mouse embryo at 9 d postcoitum (dpc) (1). The thyroid primordium buds off from the endoderm and descends during 10–15 dpc to the final position in front of the upper trachea. In the early course of thyroid morphogenesis, an invagination of the pharyngeal floor deepens and narrows to form the thyroglossal duct, which gradually undergoes atrophy as the thyroid progenitor cells move caudally. Once the sublaryngeal position has been reached, the thyroid epithelial cells start to reorganize into follicles. At this time the expression of proteins characterizing the functionally differentiated thyroid, i.e. thyroglobulin, thyroperoxidase, and sodium-iodide symporter, is initiated (2). Recently, the importance of the thyroid transcription factors-1 and -2 (TTF-1, TTF-2) and Pax8 for thyroid development has been revealed (3, 4, 5).

The location of the adult thyroid gland, distant from its site of specification, suggests that the morphogenetic process involves profound cell migration. Cells that dissociate from primitive embryonic epithelia during tissue patterning often convert to a migrating, mesenchymal cell type. This phenotypic change is known as epithelial to mesenchymal transition (EMT) and takes place, for example, in gastrulation, neural crest cell migration, and heart formation (6). EMT can be distinguished on the basis of morphological criteria including the loss of epithelial polarization and the acquisition of a flattened and elongated cell shape (7). Crucial to the EMT process is the down-regulation of cell-cell contacts, most notably E-cadherin-based adhesion (6).

The cadherin superfamily of cell-cell adhesion molecules controls a series of interactions that regulate the dissociation, migration, sorting, and reaggregation of cells during embryogenesis (8). E-Cadherin, which is one of the classical cadherins, has a critical role in the establishment of cell polarity and maintenance of the epithelial phenotype (9). Accordingly, loss of E-cadherin is considered to be a driving force when epithelial cells convert to mesenchymal cells, such as during mesoderm formation from the epiblast epithelium (10). Other classical cadherins are also involved in the reorganization of embryonic epithelia. For example, N-cadherin expression coincides with separation of the neural tube from the presumptive epidermis (11), and R-cadherin influences the mesenchymal-epithelial conversion during nephrogenesis (12). Morphogenetic actions of cadherins largely depend on homo- or heterophilic binding to corresponding molecules on adjacent cells. Hence, up- or down-regulation of cadherin expression often occurs in a distinct spatiotemporal manner that corresponds to gain or loss of cell-cell adhesion. However, signals generated by intracellular cadherin-binding proteins may also alter cellular behavior. This is most notable for ß-catenin, which, apart from linking cadherins to the cytoskeleton, is able to enter the nucleus and trans-activate target genes by interacting with tcf/lef-1 transcription factors (13, 14). Indeed, ß-catenin signaling elicited by activation of the wnt/wingless pathway is pivotal to many developmental processes in both vertebrates and invertebrates (15).

To date there are no data on the possible involvement of cell-cell adhesion molecules in thyroid development. In this study we have investigated the expression pattern of classical cadherins during mouse thyroid morphogenesis to elucidate whether an EMT-like process, typically characterized by loss of E-cadherin and up-regulation of N-cadherin, is involved. Immunohistochemical staining of embryo tissue sections showed that E-cadherin was expressed at continuously high levels throughout the entire developmental process. N-Cadherin was present in the surrounding mesenchyme, but could not at any stage be detected in the migrating thyroid anlage. Unexpectedly, R-cadherin was expressed late during thyroid development at the onset of folliculogenesis. No nuclear ß-catenin could be demonstrated in thyroid progenitor cells in the mouse embryo.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Embryos were obtained from natural matings of C57BL/6J mice. Embryonic age was estimated by considering the morning when a vaginal plug was detected as 0.5 dpc. After cervical dislocation of pregnant animals, embryos were collected at 9.5, 10.5, 12.5, and 15.5 dpc. Fully differentiated thyroid tissue was provided from the killed adult mice. Animal handling and experiments were approved by the local ethic committee at Goteborg University. All experiments were performed three times on embryos from different litters.

Immunoreagents
The following antibodies were used for immunohistochemical staining: rat mAb against E-cadherin (ECCD-2) (16), rat mAb against N-cadherin (MNCD-2) (17), rat mAb against R-cadherin (RCCD-2) (17), rabbit pAb against ß-catenin (Sigma-Aldrich Corp., St. Louis, MO), rabbit pAb against TTF-1 (Biopat, Milan, Italy), and biotin-conjugated antirat and Rhodamine Red-X-conjugated antirabbit IgG (Jackson ImmunoResearch Laboratories, West Grove, PA). Vectastain Elite ABC kit and nickel-diaminobenzidene kit (Vector Laboratories) were used for immunodetection according to the manufacturer’s instructions.

Immunohistochemistry of cadherins and TTF-1
Embryos and adult thyroid glands were fixed with 4% paraformaldehyde in 10 mM HEPES (pH 7.4) and 150 mM NaCl (HBS) overnight at 4 C. For cryoprotection of tissues, all samples were incubated overnight at 4 C in 30% sucrose solution in HBS with 1 mM CaCl2 before embedding in Tissue-Tek compound (Sakura, Zoeterwoude, The Netherlands) and freezing at -80 C. Ten-micrometer-thick sagittal sections were cut on a micron cryostat and collected on SuperFrost or polylysine glass slides (Vector Laboratories). Sections were washed in HBS, heated in a microwave oven at 700 watts until boiling (N- and R-cadherin only), postfixed in -20 C methanol with 3% H2O2 for 20 min, and blocked in Tris-buffered saline (TBS)-Ca2+ [10 mM Tris (pH 7.6), 150 mM NaCl, and 1 mM CaCl2] containing 10% fetal bovine serum (FBS) for 45 min at room temperature. Primary antibodies were added in TBS-Ca2+ supplemented with 0.2% FBS overnight at 4 C. Secondary biotin-conjugated antibody was added in TBS-Ca2+ with 0.2% FBS for 60 min at room temperature. Antibody incubations were terminated by rinsing three times in TBS-Ca2+. Immunoreactivity was detected with diaminobenzidine-nickel using the Vectastain Elite ABC kit (Vector Laboratories). Sections subjected to TTF-1 staining were permeabilized by incubation in PBS with 0.1% Triton X-100 for 20 min before being blocked in PBS with 1.5% FBS as outlined above. The sections were then incubated overnight at 4 C with TTF-1 antibody diluted in blocking buffer. Secondary Rhodamine Red-X-conjugated antibody was added in TBS-Ca2+ supplemented with 0.2% FBS for 60 min at room temperature.

Immunohistochemistry of ß-catenin
As nuclear ß-catenin immunoreactivity is known to be lost when analyzed in frozen sections (18), embryos and thyroids of adult mice were embedded in paraffin after fixation in paraformaldehyde. Sections were dewaxed in xylene, hydrated in a graded series of ethanol, and, after being washed in TBS-Ca2+, immersed in 0.01 M citrate buffer (pH 6.0) and heated in a microwave oven at 700 watts twice for 5 min each time. After cooling to room temperature, the sections were further permeabilized and blocked for 30 min in TBS-Ca2+ supplemented with 0.05% Tween 20 and 10% FBS. Immunostaining for ß-catenin was performed following the protocol used for TTF-1, as described above.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Identification of the mouse thyroid primordium during embryonic development
The developing mouse thyroid was identified by immunostaining for TTF-1, which is known to be expressed from 8.5 dpc and onward (19). Time points were chosen to study distinct stages of the developmental process: at the early specification of undifferentiated cells (9.5 dpc), the onset of precursor cell migration (10.5 dpc), the descendent migratory phase (12.5 dpc), and the terminal localization when cells start to differentiate into follicles (15.5 dpc) (20). At 9.5 dpc the thyroid primordium formed a slightly thickened area of the pharyngeal floor (Fig. 1AGo). The TTF-1-positive cells were taller than the neighboring unspecified endoderm and had a pseudostratified appearance. The subjacent mesenchyme consisted of a few cells separating the endoderm from the aortic sac. In 10.5 dpc embryos the thyroid primordium had started to move caudally as a coherent group of cells that was still connected to the endodermal lining of the pharyngeal floor by a narrow chord of stained cells probably representing the thyroglossal duct (Fig. 1BGo). At 12.5 dpc the TTF-1-positive cells were completely disconnected from the endoderm and formed a cap-like structure in close vicinity of the aorta (Fig. 1CGo); at this stage no TTF-1-positive cells bridging the gap to the pharyngeal floor could be detected. At 15.5 dpc the thyroid anlage was greatly enlarged, and cells arranged in cords appeared to organize into follicle-like structures (Fig. 1DGo). In the thyroid gland of adult mice all follicular cells expressed TTF-1 (Fig. 1EGo).



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  		FIG. 1. TTF-1 expression in the developing thyroid. A, Pharyngeal region of 9.5 dpc embryo. The nuclei of cells of the thyroid anlage are positive for TTF-1. B, 10.5 dpc embryo. C, 12.5 dpc embryo. The thyroid anlage is separated from the aorta by mesenchymal cells. D, 15.5 dpc embryo. E, Adult thyroid gland. a, Aorta; as, aortic sac; e, foregut endoderm; m, mandibular component of first branchial arch; p, pharynx; th, thyroid primordium. Scale bars, 50 µm.

 
E-Cadherin, but not N-cadherin, is expressed in the developing thyroid
The expressions of E- and N-cadherin were analyzed by immunohistochemistry on serial sections (Fig. 2Go), and parallel TTF-1 staining was regularly performed to confirm identification of the thyroid cells (not shown). In conformity with previous findings (10), the entire endoderm expressed E-cadherin that was mainly localized to the lateral cell membranes. The E-cadherin staining intensity in 9.5 dpc thyroid progenitors was similar to that in other endodermal cells (Fig. 2AGo). In 10.5 dpc embryos, cells of the budding thyroid rudiment and the thyroglossal duct were strongly positive for E-cadherin (Fig. 2CGo). Also at 12.5 dpc the thyroid cells uniformly expressed E-cadherin, in contrast to the unstained mesenchyme (Fig. 2EGo). At this stage no E-cadherin-positive cells extending toward the pharyngeal floor could be detected. E-Cadherin was also abundant in 15.5 dpc thyrocytes (Fig. 2GGo) and in the adult thyroid gland (Fig. 2IGo). There was no difference in staining intensity between centrally located cells and those demarcating the border to the surrounding mesenchyme at any time point. N-Cadherin expression could not be detected in the thyroid anlage at any stage (Fig. 2, B, D, F, H, and J). In contrast, N-cadherin staining was observed in cells surrounding the developing thyroid, most notably in the mesenchyme separating the thyroid primordium from the aortic wall at 12.5 dpc (Fig. 2FGo). N-Cadherin staining was readily detected in the heart (Fig. 2BGo) and brain (not shown), indicating antibody specificity.



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  		FIG. 2. Expression of E-cadherin (A, C, E, G, and I) and N-cadherin (B, D, F, H, and J) during thyroid morphogenesis. A and B, Pharyngeal region of 9.5 dpc embryo. E-Cadherin (A) is present along the basolateral cell surfaces of the foregut endoderm. The endoderm is negative for N-cadherin (B), whereas the heart is clearly stained. C and D, 10.5 dpc embryo. E and F, 12.5 dpc embryo. N-Cadherin (F) is expressed in the mesenchyme surrounding the aorta. G and H, 15.5 dpc embryo. A few N-cadherin-positive (H) nerve fibers are seen. I and J, Adult thyroid gland. a, Aorta; as, aortic sac; e, foregut endoderm; h, heart; m, mesenchyme; th, thyroid primordium. Scale bar, 50 µm.

 
Expression of R-cadherin coincides with the onset of thyroid folliculogenesis
Previous studies suggest that R-cadherin is involved in epithelial morphogenesis in other organs. For example, in the embryonic kidney R-cadherin is important for correct patterning and branching of the ureteric bud epithelium (12). It was therefore of interest to investigate whether R-cadherin is expressed during thyroid development. R-Cadherin was not detected in the thyroid or its immediate surroundings at 12.5 dpc or earlier (Fig. 3Go, A and B). However, at 15.5 dpc the thyroid cells showed a strong staining intensity (Fig. 3CGo) comparable to that of, for instance, thymus and kidney (data not shown), previously known to express R-cadherin (21). Also, adult thyroid follicular cells expressed R-cadherin (Fig. 3DGo). In all instances, R-cadherin immunoreactivity was largely confined to cell-cell contacts.



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  		FIG. 3. R-Cadherin expression during thyroid development. A, Pharyngeal region of 9.5 dpc embryo. R-Cadherin is not detected in the foregut endoderm. B, 12.5 dpc embryo. R-Cadherin is not detected in the thyroid primordium. C, 15.5 dpc embryo. R-Cadherin is expressed at cell-cell contacts of thyroid progenitor cells. D, Adult thyroid gland. R-Cadherin is concentrated at basolateral surfaces of follicular cells. a, Aorta; as, aortic sac; e, foregut endoderm; th, thyroid primordium. Scale bar, 50 µm.

 
ß-Catenin is confined to cell-cell contacts throughout thyroid organogenesis
Cadherins are able to modulate ß-catenin signaling to the nucleus by sequestering ß-catenin to the plasma membrane. The finding of another classical cadherin expressed during late thyroid morphogenesis in addition to the constant presence of E-cadherin prompted us to investigate whether this change might be accompanied by an alteration in the subcellular localization of ß-catenin. By immunohistochemistry on paraffin sections ß-catenin was found to be located mainly along the lateral cell membranes of the entire foregut endoderm (Fig. 4AGo), including the 9.5 dpc thyroid precursor cells. The cytoplasm was faintly stained, and no nuclear accumulation of ß-catenin could be detected. Likewise, ß-catenin was restricted to areas of cell-cell contact, whereas the nuclei remained unstained in later stages of thyroid embryonic development (Fig. 4Go, B and C) as well as in the adult thyroid gland (Fig. 4DGo).



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  		FIG. 4. ß-Catenin expression during thyroid morphogenesis. A, Pharyngeal region of 9.5 dpc embryo. ß-Catenin is present at basolateral cell surfaces in the entire foregut endoderm. B–D, 12.5 and 15.5 dpc embryos and adult thyroid gland. ß-Catenin is confined to cell-cell contacts at all time points. a, Aorta; as, aortic sac; e, foregut endoderm; th, thyroid primordium. Scale bar, 30 µm.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The thyroid gland is unique among the endodermally derived organs in that it has no connection with the gut tube and is located rather distant from where it was specified. This suggests that thyroid development might involve more active cell migration than the common theme of budding-branching morphogenesis of other endodermal derivatives, such as lung, liver, and pancreas (22, 23, 24). However, the effector mechanisms regulating the dislocation of the thyroid anlage from the pharyngeal endoderm, its further migration, and the terminal differentiation of the follicular epithelium are largely unknown. We therefore investigated whether the early phase of thyroid development comprises a transient phenotypic conversion to a more mesenchymal and migrating phenotype similar to that known to occur during, for example, gastrulation, neural crest migration, and heart formation (25, 26, 27). Such loss of the epithelial phenotype involves down-regulation of E-cadherin, a hallmark of EMT taking place in embryogenesis (6). Contrary to this, we found that the thyroid primordium maintained E-cadherin expression at all stages, and that E-cadherin colocalized with ß-catenin at the cell-cell contacts. Moreover, the thyroid progenitor cells had an epithelial shape and were tightly connected throughout the descent. This indicates that embryonic thyrocytes maintain their original epithelial differentiation and homotypic cell-cell adhesion mediated by E-cadherin. The cells might therefore not be actively motile, but may rather reach their destination by passive translocation along with adjacent tissues.

Although the presence of E-cadherin strongly supports that the epithelial phenotype is maintained, other factors may interfere with this function. In vitro experiments indicate that coexpression of N-cadherin is able to overrule E-cadherin-mediated adhesion and promote cell migration (28). This is most obvious in tumor cell lines in which N-cadherin is associated with a more invasive behavior (29). N-Cadherin is also known to modulate the embryonic development of many organs apart from neural tissue, e.g. during gastrulation when epiblast cells lose their epithelial morphology and start to migrate to form mesoderm (11). Notably, organs of endodermal origin, such as lung, liver, and pancreas, transiently express N-cadherin early during morphogenesis (30). Recent findings of N-cadherin induction in primary cultured adult thyrocytes undergoing EMT in response to growth factors (31) indicate that the necessary transcriptional control elements are present in thyrocytes. It was therefore of interest to investigate whether N-cadherin was expressed during thyroid development. However, no N-cadherin immunoreactivity was found in mouse thyroid progenitor cells at any time between the endodermal specification at 9.5 dpc and the start of terminal differentiation at 15.5 dpc. This suggests that N-cadherin probably has no direct role in the migration of the embryonic thyroid tissue.

If thyroid precursor cells do not actively migrate, how do they ultimately reach their final destination? Earlier studies on thyroid development in chick and mice embryos employing scanning electron microscopy have suggested that the thyroid anlage might be carried along with the caudal movement of the heart and major vessels (20). We found a close spatial relationship between the thyroid and the primitive aorta in 12.5 dpc embryos. Moreover, the mesenchyme separating the cap-formed thyroid from the adjacent vessel expressed N-cadherin. This suggests that epithelial-mesenchymal interactions might be of significance to the morphogenetic process. It is notable that the development of other organs that bud from the endodermal lining is probably controlled by paracrine signals from the surrounding mesenchyme (32). Interestingly, a role for N-cadherin in epithelial-mesenchymal interactions has recently been recognized in pancreatic development (33); genetic deletion of N-cadherin, which is normally expressed in the surrounding mesenchyme, selectively causes dorsal pancreas agenesis. This suggests that N-cadherin indirectly acts as a survival factor for the parenchymal cells. Whether mesenchymal N-cadherin takes part in the translocation of the developing thyroid remains an open question.

In this work we demonstrate for the first time that thyroid cells express R-cadherin. This adhesion molecule belongs to the classical cadherin subfamily and shows strong sequence homology with N-cadherin. R-Cadherin was first detected at 15.5 dpc, coinciding with the onset of folliculogenesis and the expression of organ-specific proteins such as thyroglobulin and the TSH receptor (19). Interestingly, R-cadherin immunoreactivity was also abundant in the adult thyroid, suggesting that it might contribute to the mechanisms that determine the terminally differentiated phenotype of the follicular epithelium. However, the precise functions of R-cadherin in other tissues are still largely unknown. In the central nervous system, the expression of R-cadherin is linked to the guidance of axon growth (34). There are also some indications that R-cadherin is involved in epithelial differentiation. For example, in teratomas derived from E-cadherin-negative embryonic stem cells R-cadherin rescues the capacity of these pluripotent cells to form epithelia (21). In kidney embryogenesis, R-cadherin is functionally involved in the branching and patterning of the ureteric bud epithelium and the conversion of the metanephric mesenchyme into renal tubular epithelium (12). It is therefore of interest to investigate the possible role of R-cadherin in late development of the thyroid using R-cadherin knockout mice.

The neoexpression of R-cadherin in thyroid progenitor cells at the onset of terminal differentiation suggests that intercellular adhesion previously mediated by E-cadherin is reinforced. As both cadherins bind ß-catenin, it is possible that they conjointly increase the sequestration of ß-catenin to the adherens junctions. Conversely, it can be hypothesized that in cells lacking R-cadherin the level of cytosolic ß-catenin might be increased or more easily mobilized. As nuclear translocation of ß-catenin after activation of the wnt/wingless signaling pathway has been demonstrated in several tissues during embryogenesis (35, 36), it was of interest to investigate whether this takes place in the thyroid as well. ß-Catenin was readily detected at the thyroid cell-cell contacts, almost entirely overlapping with the distribution of E-cadherin, and no nuclear accumulation could be found at any time point. It is therefore unlikely that canonical wnt signaling has a role in the specification and migration of the thyroid anlage. Also, the coexpression of R- and E-cadherin in late thyroid development does not seem to involve altered ß-catenin function.

In conclusion, thyroid development is probably influenced by at least two classical cadherins. The finding of continuous expression of E-cadherin in thyroid progenitor cells demonstrates that the epithelial differentiation is maintained throughout the entire morphogenetic process, whereas the onset of R-cadherin expression in late thyroid development proposes a functional role in follicle formation. The lack of EMT suggests that thyroid morphogenesis does not primarily involve active cell migration.


   Acknowledgments
 
We are grateful to Prof. Jan-Olof Karlsson and Ann Kling-Petersen for generously sharing laboratory equipment and advice, and to Prof. Lars E. Ericson for valuable comments.


   Footnotes
 
This work was supported by the Swedish Research Council (12X-537), the Goteborg Medical Society, and the Kungliga Vetenskaps-och Vitterhetssamhället, Goteborg.

H.F. and M.G. contributed equally to this study.

Abbreviations: dpc, Days postcoitum; EMT, epithelial to mesenchymal transition; FBS, fetal bovine serum; TBS, Tris-buffered saline; TTF, thyroid transcription factor.

Received March 27, 2003.

Accepted for publication April 29, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Romert P, Gauguin J 1973 The early development of the median thyroid gland of the mouse. A light-, electron-microscopic and histochemical study. Z Anat Entwicklungsgesch 139:319–336[CrossRef][Medline]
  2. Missero C, Cobellis G, De Felice M, Di Lauro R 1998 Molecular events involved in differentiation of thyroid follicular cells. Mol Cell Endocrinol 140:37–43[CrossRef][Medline]
  3. Kimura S, Hara Y, Pineau T, Fernandez-Salguero P, Fox CH, Ward JM, Gonzalez FJ 1996 The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary. Genes Dev 10:60–69[Abstract/Free Full Text]
  4. De Felice M, Ovitt C, Biffali E, Rodriguez-Mallon A, Arra C, Anastassiadis K, Macchia PE, Mattei MG, Mariano A, Scholer H, Macchia V, Di Lauro R 1998 A mouse model for hereditary thyroid dysgenesis and cleft palate. Nat Genet 19:395–398[CrossRef][Medline]
  5. Mansouri A, Chowdhury K, Gruss P 1998 Follicular cells of the thyroid gland require Pax8 gene function. Nat Genet 19:87–90[CrossRef][Medline]
  6. Savagner P 2001 Leaving the neighborhood: molecular mechanisms involved during epithelial-mesenchymal transition. BioEssays 23:912–923[CrossRef][Medline]
  7. Hay ED 1995 An overview of epithelio-mesenchymal transformation. Acta Anat 154:8–20[Medline]
  8. Tepass U, Truong K, Godt D, Ikura M, Peifer M 2000 Cadherins in embryonic and neural morphogenesis. Nat Rev Mol Cell Biol 1:91–100[CrossRef][Medline]
  9. Vleminckx K, Kemler R 1999 Cadherins and tissue formation: integrating adhesion and signaling. BioEssays 21:211–220[CrossRef][Medline]
  10. Thiery JP, Delouvee A, Gallin WJ, Cunningham BA, Edelman GM 1984 Ontogenetic expression of cell adhesion molecules: L-CAM is found in epithelia derived from the three primary germ layers. Dev Biol 102:61–78[CrossRef][Medline]
  11. Hatta K, Takeichi M 1986 Expression of N-cadherin adhesion molecules associated with early morphogenetic events in chick development. Nature 320:447–449[CrossRef][Medline]
  12. Dahl U, Sjodin A, Larue L, Radice GL, Cajander S, Takeichi M, Kemler R, Semb H 2002 Genetic dissection of cadherin function during nephrogenesis. Mol Cell Biol 22:1474–1487[Abstract/Free Full Text]
  13. Behrens J, von Kries JP, Kuhl M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W 1996 Functional interaction of ß-catenin with the transcription factor LEF-1. Nature 382:638–642[CrossRef][Medline]
  14. He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW 1998 Identification of c-MYC as a target of the APC pathway. Science 281:1509–1512[Abstract/Free Full Text]
  15. Peifer M, Polakis P 2000 Wnt signaling in oncogenesis and embryogenesis-a look outside the nucleus. Science 287:1606–1609[Abstract/Free Full Text]
  16. Shirayoshi Y, Hatta K, Hosoda M, Tsunasawa S, Sakiyama F, Takeichi M 1986 Cadherin cell adhesion molecules with distinct binding specificities share a common structure. EMBO J 5:2485–248[Medline]
  17. Matsunami H, Takeichi M 1995 Fetal brain subdivisions defined by R- and E-cadherin expressions: evidence for the role of cadherin activity in region-specific, cell-cell adhesion. Dev Biol 172:466–478[CrossRef][Medline]
  18. Munne A, Fabre M, Marinoso ML, Gallen M, Real FX 1999 Nuclear ß-catenin in colorectal tumors: to freeze or not to freeze? Colon Cancer Team at IMAS. J Histochem Cytochem 47:1089–1094[Abstract/Free Full Text]
  19. Lazzaro D, Price M, de Felice M, Di Lauro R 1991 The transcription factor TTF-1 is expressed at the onset of thyroid and lung morphogenesis and in restricted regions of the foetal brain. Development 113:1093–1104[Abstract]
  20. Hilfer SR, Brown JW 1984 The development of pharyngeal endocrine organs in mouse and chick embryos. Scan Electron Microsc 4:2009–2022
  21. Rosenberg P, Esni F, Sjodin A, Larue L, Carlsson L, Gullberg D, Takeichi M, Kemler R, Semb H 1997 A potential role of R-cadherin in striated muscle formation. Dev Biol 187:55–70[CrossRef][Medline]
  22. Edlund H 1999 Pancreas: how to get there from the gut? Curr Opin Cell Biol 11:663–668[CrossRef][Medline]
  23. Warburton D, Schwarz M, Tefft D, Flores-Delgado G, Anderson KD, Cardoso WV 2000 The molecular basis of lung morphogenesis. Mech Dev 92:55–81[CrossRef][Medline]
  24. Zaret KS 2002 Regulatory phases of early liver development: paradigms of organogenesis. Nat Rev Genet 3:499–512[CrossRef][Medline]
  25. Burdsal CA, Damsky CH, Pedersen RA 1993 The role of E-cadherin and integrins in mesoderm differentiation and migration at the mammalian primitive streak. Development 118:829–844[Abstract]
  26. Erickson CA, Perris R 1993 The role of cell-cell and cell-matrix interactions in the morphogenesis of the neural crest. Dev Biol 159:60–74[CrossRef][Medline]
  27. Nakajima Y, Yamagishi T, Hokari S, Nakamura H 2000 Mechanisms involved in valvuloseptal endocardial cushion formation in early cardiogenesis: roles of transforming growth factor (TGF)-ß and bone morphogenetic protein (BMP). Anat Rec 258:119–127[CrossRef][Medline]
  28. Hazan RB, Phillips GR, Qiao RF, Norton L, Aaronson SA 2000 Exogenous expression of N-cadherin in breast cancer cells induces cell migration, invasion, and metastasis. J Cell Biol 148:779–790[Abstract/Free Full Text]
  29. Islam S, Carey TE, Wolf GT, Wheelock MJ, Johnson KR 1996 Expression of N-cadherin by human squamous carcinoma cells induces a scattered fibroblastic phenotype with disrupted cell-cell adhesion. J Cell Biol 135:1643–1654[Abstract/Free Full Text]
  30. Hatta K, Takagi S, Fujisawa H, Takeichi M 1987 Spatial and temporal expression pattern of N-cadherin cell adhesion molecules correlated with morphogenetic processes of chicken embryos. Dev Biol 120:215–227[CrossRef][Medline]
  31. Grande M, Franzen A, Karlsson JO, Ericson LE, Heldin NE, Nilsson M 2002 Transforming growth factor-ß and epidermal growth factor synergistically stimulate epithelial to mesenchymal transition (EMT) through a MEK-dependent mechanism in primary cultured pig thyrocytes. J Cell Sci 115:4227–4236[Abstract/Free Full Text]
  32. Roberts DJ 2000 Molecular mechanisms of development of the gastrointestinal tract. Dev Dyn 219:109–120[CrossRef][Medline]
  33. Esni F, Johansson BR, Radice GL, Semb H 2001 Dorsal pancreas agenesis in N-cadherin-deficient mice. Dev Biol 238:202–212[CrossRef][Medline]
  34. Treubert-Zimmermann U, Heyers D, Redies C 2002 Targeting axons to specific fiber tracts in vivo by altering cadherin expression. J Neurosci 22:7617–7626[Abstract/Free Full Text]
  35. Smalley MJ, Dale TC 1999 Wnt signalling in mammalian development and cancer. Cancer Metastasis Rev 18:215–230[CrossRef][Medline]
  36. Eberhart CG, Argani P 2001 Wnt signaling in human development: ß-catenin nuclear translocation in fetal lung, kidney, placenta, capillaries, adrenal, and cartilage. Pediatr Dev Pathol 4:351–357[CrossRef][Medline]



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