Transforming growth factor-β3 regulates transdifferentiation of medial edge epithelium during palatal fusion and associated degradation of the basement membrane

Kaartinen, Vesa; Cui, Xiao Mei; Heisterkamp, Nora; Groffen, John; Shuler, Charles F.

doi:10.1002/(sici)1097-0177(199707)209:3<255::aid-aja1>3.0.co;2-h

Cited by 151 publications

(63 citation statements)

References 22 publications

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“…Analogously, loss of function mutations in MSX1 have been found in patients with cleft palate, and PAX9 has been associated with human clefting (41,42). Mutant mice lacking Transforming growth factor β3 (Tgfβ3) exhibit an isolated cleft palate, and this is characterized by defects in the fusion process of the palatal shelves (43)(44)(45). Interestingly the expression patterns of Fgfr2b and Shh overlaps with that of Tgfβ3.…”

Section: Discussionmentioning

confidence: 99%

Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate

Rice

Spencer‐Dene²,

Connor³

et al. 2004

J. Clin. Invest.

320

371

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Classical research has suggested that early palate formation develops via epithelial-mesenchymal interactions, and in this study we reveal which signals control this process. Using Fgf10 -/-, FGF receptor 2b -/-(Fgfr2b -/-), and Sonic hedgehog (Shh) mutant mice, which all exhibit cleft palate, we show that Shh is a downstream target of Fgf10/Fgfr2b signaling. Our results demonstrate that mesenchymal Fgf10 regulates the epithelial expression of Shh, which in turn signals back to the mesenchyme. This was confirmed by demonstrating that cell proliferation is decreased not only in the palatal epithelium but also in the mesenchyme of Fgfr2b -/-mice. These results reveal a new role for Fgf signaling in mammalian palate development. We show that coordinated epithelial-mesenchymal interactions are essential during the initial stages of palate development and require an Fgf-Shh signaling network.

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Section: Discussionmentioning

confidence: 99%

Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate

Rice

Spencer‐Dene²,

Connor³

et al. 2004

J. Clin. Invest.

320

371

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“…In Tgfb3-null mutants, palatal shelf adhesion occurs, but impaired apoptosis causes persistence of the MES resulting in non-union of the palatal mesenchyme. Treatment of these mice with recombinant TGF-b3 or overexpression of Smad2 rescues palate fusion (Kaartinen et al 1997;Taya et al 1999;Cui et al 2005;Dudas et al 2006;Xu et al 2006). BMP signaling regulates specification and migration of cranial neural crest cells to the facial primordia (reviewed in Nie et al 2006), and also controls mesenchymal cell proliferation.…”

Section: Digit Malformations Caused By Disruption Of Tgf-b and Bmp Simentioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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The transforming growth factor b (TGF-b) family of signaling molecules, which includes TGF-bs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-b family members play different roles in these tissues, and their activities are often balanced with those of other TGF-b family members and by interactions with other signaling pathways. Perturbations in TGF-b family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-b family of signaling mediators and the extracellular matrix in connective tissues.T he transforming growth factor b (TGF-b) family of cytokines comprises the three TGF-b proteins (TGF-b1, TGF-b2, and TGFb3) and related growth and differentiation factors such as activins, inhibins, bone morphogenic proteins (BMPs), and growth and differentiation factors (GDFs). These molecules play critical roles both in normal development and in several pathological conditions, including inflammation, fibrosis, and cancer (reviewed in Li and Flavell 2006;Gordon and Blobe 2008;Ikushima and Miyazono 2010). This review focuses on the role of these proteins in development and homeostasis of the skeleton and other connective tissues (summarized in Fig. 1) and on the diseases that ensue when these pathways are altered. Aberrant signaling in these pathways has been associated with common connective 6 These authors contributed equally to this work.

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“…Those favoring epithelial-mesenchymal transformation as the major mechanism propose that apoptosis is restricted to the periderm layer and suggest that this is important for the initial adhesion of the palatal shelf epithelia. Tgf␤3 has been proposed to induce epithelial-mesenchymal transformation of the palatal MEE (Kaartinen et al, 1997;Sun et al, 1998;reviewed in Nawshad et al, 2004). However, recent fate mapping of the mouse palatal MEE cells using the Cre/loxP-mediated in vivo lineage tracing method has ruled out MEE contribution to the palatal mesenchyme (Vaziri Sani et al, 2005).…”

Section: Molecular and Cellular Mechanisms Underlying The Aberrant Ormentioning

confidence: 99%

Jag2‐Notch1 signaling regulates oral epithelial differentiation and palate development

Casey

Lan

Cho

et al. 2006

Developmental Dynamics

122

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During mammalian palatogenesis, palatal shelves initially grow vertically from the medial sides of the paired maxillary processes flanking the developing tongue and subsequently elevate and fuse with each other above the tongue to form the intact secondary palate. Pathological palate-mandible or palate-tongue fusions have been reported in humans and other mammals, but the molecular and cellular mechanisms that prevent such aberrant adhesions during normal palate development are unknown. We previously reported that mice deficient in Jag2, which encodes a cell surface ligand for the Notch family receptors, have cleft palate associated with palate-tongue fusions. In this report, we show that Jag2 is expressed throughout the oral epithelium and is required for Notch1 activation during oral epithelial differentiation. We show that Notch1 is normally highly activated in the differentiating oral periderm cells covering the developing tongue and the lateral oral surfaces of the mandibular and maxillary processes during palate development. Oral periderm activation of Notch1 is significantly attenuated during palate development in the Jag2 mutants. Further molecular and ultrastructural analyses indicate that oral epithelial organization and periderm differentiation are disrupted in the Jag2 mutants. Moreover, we show that the Jag2 mutant tongue fused to wild-type palatal shelves in recombinant explant cultures. These data indicate that Jag2-Notch1 signaling is spatiotemporally regulated in the oral epithelia during palate development to prevent premature palatal shelf adhesion to other oral tissues and to facilitate normal adhesion between the elevated palatal shelves.

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Transforming growth factor-β3 regulates transdifferentiation of medial edge epithelium during palatal fusion and associated degradation of the basement membrane

Cited by 151 publications

References 22 publications

Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate

Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

Jag2‐Notch1 signaling regulates oral epithelial differentiation and palate development

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