Transforming growth factor β (TGFβ) signalling in palatal growth, apoptosis and epithelial mesenchymal transformation (EMT)

doi:10.1016/j.archoralbio.2004.05.007

Archives of Oral Biology

Volume 49, Issue 9, September 2004, Pages 675-689

https://doi.org/10.1016/j.archoralbio.2004.05.007 Get rights and content

Abstract

Formation of the medial edge epithelial (MEE) seam by fusing the palatal shelves is a crucial step of palate development. The opposing shelves adhere to each other at first by adherens junctions, then by desmosomes in the MEE. The MEE seam disappears by epithelial mesenchymal transformation (EMT), which creates confluence of connective tissue across the palate. Cleft palate has a mutifactorial etiology that often includes failure of adherence of apposing individual palatal shelves and/or EMT of the MEE. In this review, we first discuss TGFβ^# biology, including functions of TGFβ isoforms, receptors, down stream transcription factors, endosomes, and signalling pathways. Different isoforms of the TGFβ family play important roles in regulating various aspects of palate development. TGFβ₁ and TGFβ₂ are involved in growth, but it is TGFβ₃ that regulates MEE transformation to mesenchyme to bring about palatal confluence. Its absence results in cleft palate. Understanding of TGFβ family signalling is thus essential for development of therapeutic strategies. Because TGFβ₃ and its downstream target, LEF1, play the major role in epithelial transformation, it is important to identify the signalling pathways they use for palatal EMT. Here, we will discuss in detail the mechanisms of palatal seam disappearance in response to TGFβ₃ signalling, including the roles, if any, of growth and apoptosis, as well as EMT in successful MEE adherence and seam formation. We also review recent evidence that TGFβ₃ uses Smad2 and 4 during palatal EMT, rather than β-Catenin, to activate LEF1. TGFβ₁ has been reported to use non-Smad signalling using RhoA or MAPKinases in vitro, but these are not involved in activation of palatal EMT in situ. A major aim of this review is to document the genetic mechanisms that TGFβ uses to bring about palatal EMT and to compare these with EMT mechanisms used elsewhere.

Introduction

Transforming growth factor (TGF) β₃ was shown almost 10 years ago to play an essential role in palatogenesis by the observation that palates fail to fuse in TGFβ₃ null mice.1., 2. In the null mutants, cleft palate arises from failure of adherence of the paired shelves.¹ Exogenous TGFβ₃ subsequently was shown to induce conversion of the fused palatal seam in TGFβ₃ null chickens to connective tissue by epithelial mesenchymal transformation (EMT), thus creating palatal confluence.³ Treatment of mouse palates with antisense ODNs to TGFβ₃ prevents fusion.⁴ Clefting of the human palate is a frequently encountered congenital deformity that may result from failure of palatal growth and elevation, as well as EMT.³ The signalling pathways used by TGFβ₃ for successful palatal EMT have received much attention in recent years and will be the main subject of this section. Hopefully, knowledge of these pathways will lead to better understanding of cleft palate and more effective treatment.

Palatogenesis is remarkably similar among vertebrates.⁵ In the mouse, the palatal shelves grow out bilaterally from the internal surfaces of the maxillary processes. They elongate on either side of the tongue, and then become horizontal above the tongue as it descends. When the opposing shelves approach each other (Fig. 1A), the cells of the outer layer (periderm) of the opposed medial edge epithelia (MEE) undergo apoptosis and slough off, exposing the lateral surfaces of the underlying basal MEE cells for close contact with each other, thus promoting formation of the midline and nasopalatine seams (arrowheads, Figure 1, Figure 2). The seams subsequently undergo EMT resulting in connective tissue confluence (Figure 1, Figure 2).6., 7. TGFβ family members are involved in many biological processes during palatogenesis, such as cell migration, EMT, extracellular matrix (ECM) synthesis and deposition, degradation of basement membrane,⁸ cell proliferation, and apoptosis.⁹ The role of various TGFβ isoforms in palate formation is still under investigation. Only TGFβ₃ orchestrates fusion of the palatal shelves by EMT of the MEE seam.6., 7., 10., 11. Other isoforms of the TGFβ family (TGFβ₁ and TGFβ₂) do not play a major role in palate EMT,⁴ but TGFβ₁ is able to activate EMT in MDCK cells.¹² In this review, we consider in detail the signalling mechanisms used by these basic members of the TGFβ family.

Section snippets

Function of TGFβ family isoforms in palatogenesis

The TGFβ family consists of more than 30 ligand proteins, regulating a wide variety of biological process such as proliferation, differentiation,¹³ EMT,³ and apoptosis.¹⁴ Although the three isoforms (TGFβ₁, TGFβ₂, and TGFβ₃) share 71–76% sequence identity, signal through Smads or MAPKs, and are highly conserved between species, the phenotypes resulting from the knockout of these mammalian TGFβ isoforms are very distinct and are not overlapping.¹⁵ This indicates that these ligands have isoform

Receptor activation by the TGFβ family: role of endosomes

Because these different isoforms can bind to the same receptors, one might expect them to have similar activity, but this is not true, as we have discussed above. To activate these receptors, the autocrine TGFβ molecules are secreted. The TGFβ homodimer signals through transmembrane serine/threonine kinase receptors (Tβr) designated as TGFβ type I (TβrI), type II (TβrII), and type III (TβrIII) that play crucial roles during palate development.²⁵ However, only TβrI and TβrII are signalling

Smad dependent signalling: role of SARA

After the activated Tβr complex is internalised, it interacts with downstream signalling molecules at discrete endocytic locations. TβrI colocalizes with several receptor interacting proteins that exert important functions in subcellular localisation of Smad proteins.³⁶ Under ideal conditions, Smad phosphorylation and transport to the nucleus is facilitated by Tβrs,³⁷ early endosomes,³⁸ phosphotidylinositol-3-kinase (PI3K)³⁹ and Smad anchor for receptor activation (SARA).40., 41. SARA is a

Smad dependent signalling: activation of LEF1

The phosphorylation of Smad2 (or Smad3) and formation of a heteromeric complex with Smad4 leads to nuclear translocation of this Smad2/4 heterodimer, where it binds strongly with the Smad binding element (SBE) domain of the transcription factor lymphoid enhancing factor-1 (LEF1) gene. In the palate, nuclear Smad2/4 stimulates LEF1 mRNA synthesis mediated by TGFβ₃ and also subsequently activates the LEF1 protein to stimulate EMT.⁴⁶ This study by Nawshad and Hay⁴⁶ establishes that only Smad

Smad independent signalling

In certain situations where the Smad dependent pathway is either not activated or blocked, it may be possible to induce gene transcription through a G-protein signalling cascade. There is moderate evidence in vitro that TGFβ induces mesenchyme like cells independent of Smads, using the Ras-Raf-MEK-ERK signalling pathway in pancreatic cancer cell lines⁵⁶ and the human cancer cell lines⁵⁷ via RhoA-Rac MAP kinase pathways.58., 59. However, the EMT described was not proven to produce migrating

Epithelial-mesenchymal transformation (EMT): TGFβ₃ signals EMT target genes via LEF1 and Smads

The evidence for EMT of the basal cells of the MEE consists of cytological descriptions using electron microscopy and light microscopy cell tracing to follow stages in the development of the rodent palate in vivo.⁶ While the periderm (outer layer) of the MEE begins to die and sloughs off when the shelves assume horizontal position, the basal MEE cells retain robust morphology⁶ and can soon be seen to break away from the each other while assuming the fusiform morphology of mesenchymal cells. In

Role of periderm apoptosis

Although most researchers are in accord about the function and localisation of TGFβ isoforms, there are differences in opinion about the involvement of apoptosis during palate development. It is, therefore, important to elaborate the apoptotic function during palate development. While some believe that dissociation and disappearance of the MEE seam is caused by cell death,21., 73., 74. it is likely that their data are the result of accidentally trapping dying periderm in the seam when palates

Overview of studies of TGFβ signalling in palate development

Palate development, as well as development in general, is synchronised and controlled by numerous factors including growth factors, such as TGFβ₁–TGFβ₃. TGFβ family molecules have been shown to play an important role in regulating growth, differentiation and EMT during various stages of palate development. TGFβ₃ has a late role (11–16.5 dpc) in MEE cells; particularly in palatal shelve fusion and EMT, whereas TGFβ₁ and TGFβ₂ stimulate DNA synthesis and proliferation from early stages of palate

Conclusion

The developing rodent palate MEE seam has been in recent years, the best model for the study of TGFβ signal transduction during EMT in an embryonic organ in situ. After sloughing of the outer layer of the MEE (periderm), the healthy basal cells of the MEE begin (12 h after shelves adhere) to express robust nuclear Smads that upregulate LEF1 gene expression and then activate the LEF1 transcription factor. The newly discovered function of TGFβ₃, where Smad2/4, not β-Catenin or plakoglobin, is the

Acknowledgements

The original research described in this review was supported by NIH R01-DE11142 from the US public health service. We thank Caroline Chui for her help preparing the manuscript and figures.

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^#: TGFβ refers to both the human and murine growth factor in this review.

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REVIEWTransforming growth factor β (TGFβ) signalling in palatal growth, apoptosis and epithelial mesenchymal transformation (EMT)

Abstract

Introduction

Section snippets

Function of TGFβ family isoforms in palatogenesis

Receptor activation by the TGFβ family: role of endosomes

Smad dependent signalling: role of SARA

Smad dependent signalling: activation of LEF1

Smad independent signalling

Epithelial-mesenchymal transformation (EMT): TGFβ3 signals EMT target genes via LEF1 and Smads

Role of periderm apoptosis

Overview of studies of TGFβ signalling in palate development

Conclusion

Acknowledgements

Dev. Biol.

Dev. Biol.

Dev. Biol.

J. Biol. Chem.

Dev. Biol.

Differentiation

Dev. Biol.

Dev. Biol.

Dev. Biol.

Cell

Biochim. Biophys. Acta

Cell

Trends Biochem. Sci.

Cell Signal

Mol. Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Cell

J. Biol. Chem.

Semin. Cell Dev. Biol.

Cell Biol. Int.

Curr. Opin. Cell Biol.

Exp. Cell Res.

Cytokine Growth Factor Rev.

Cytokine Growth Factor Rev.

J. Biol. Chem.

Dev. Biol.

Dev. Biol.

Dev. Biol.

J. Biol. Chem.

Transforming growth factor-beta 3 is required for secondary palate fusion

Nat. Genet.

The transforming growth factor-beta 3 knock-out mouse: an animal model for cleft palate

Plast. Reconstr. Surg.

TGFbeta3 promotes transformation of chicken palate medial edge epithelium to mesenchyme in vitro

Development

Inhibition of TGF-beta 3 (but not TGF-beta 1 or TGF-beta 2) activity prevents normal mouse embryonic palate fusion

Int. J. Dev. Biol.

Developmental aspects of secondary palate formation

J. Embryol. ExpMorphol.

Epithelial-mesenchymal transformation during palatal fusion: carboxyfluorescein traces cells at light and electron microscopic levels

Development

Transforming growth factor-beta3 regulates transdifferentiation of medial edge epithelium during palatal fusion and associated degradation of the basement membrane

Dev. Dyn.

Simultaneous loss of expression of syndecan-1 and E-cadherin in the embryonic palate during epithelial-mesenchymal transformation

Int. J. Dev. Biol.

Physiological actions and clinical applications of transforming growth factor-beta (TGF-beta)

Growth Factors

REVIEW
Transforming growth factor β (TGFβ) signalling in palatal growth, apoptosis and epithelial mesenchymal transformation (EMT)

Epithelial-mesenchymal transformation (EMT): TGFβ₃ signals EMT target genes via LEF1 and Smads