Epithelial and ectomesenchymal role of the type I TGF-β receptor ALK5 during facial morphogenesis and palatal fusion

Dudáš, Marek; Kim, Jieun; Li, Wai Yee; Nagy, Andre; Larsson, Jonas; Karlsson, Stefán; Chai, Yang; Kaartinen, Vesa

doi:10.1016/j.ydbio.2006.05.030

Cited by 137 publications

(173 citation statements)

References 95 publications

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“…Before palatal shelf elevation, epithelial expression of TGF-b1 and TGF-b3 is induced within the future adhesion site, and then diminishes during disintegration of the MES (Cui et al 1998;Cui and Shuler 2000;Yang and Kaartinen 2007;Bush and Jiang 2012). Global ablation of TGF-b2 or TGF-b3 ligands or cranial neural crest specific knockout of Tgfbr2 or Tgfbr1 causes cleft palate, highlighting the importance of this signaling pathway in palatogenesis (Kaartinen et al 1995;Proetzel et al 1995;Sanford et al 1997;Ito et al 2003;Dudas et al 2006;Xu et al 2006). In Tgfb3-null mutants, palatal shelf adhesion occurs, but impaired apoptosis causes persistence of the MES resulting in non-union of the palatal mesenchyme.…”

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

confidence: 99%

“…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%

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

confidence: 99%

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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“…These, in parallel with the transcription factors Snai1 and Snai2, promote MES apoptosis and disintegration. 6,21,[39][40][41][42][43] Our results demonstrated that not only the Tgfβ-pathway genes but also other pathway-related genes might interact each other to regulate medial edge epithelium disintegration and complete palatogenesis (Supplementary Figure 2) In several studies, it has been suggested that there is a gene-environment interaction exists between smoking and TGFα expression for the induction of cleft palate. 8,25,[44][45][46][47][48][49] By using our microarray analysis and filtering cleft palate-related genes, we determined that nicotine is the highly susceptible element of smoking to induce down-regulation of TGFα, which may explain the palatal size abnormality observed in nicotine-treated pups.…”

Section: Discussionmentioning

confidence: 64%

Nicotine Exposure During Pregnancy Results in Persistent Midline Epithelial Seam With Improper Palatal Fusion

Öztürk

Sheldon

Sharma

et al. 2015

NICTOB

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Introduction: Nonsyndromic cleft palate is a common birth defect (1:700) with a complex etiology involving both genetic and environmental risk factors. Nicotine, a major teratogen present in tobacco products, was shown to cause alterations and delays in the developing fetus. Methods: To demonstrate the postpartum effects of nicotine on palatal development, we delivered three different doses of nicotine (1.5, 3.0, and 4.5 mg/kg/d) and sterile saline (control) into pregnant BALB/c mice throughout their entire pregnancy using subcutaneous micro-osmotic pump. Dams were allowed to deliver (~day 21 of pregnancy) and neonatal assessments (weight, length, nicotine levels) were conducted, and palatal tissues were harvested for morphological and molecular analyses, as well as transcriptional profiling using microarrays. Results: Consistent administration of nicotine caused developmental retardation, still birth, low birth weight, and significant palatal size and shape abnormality and persistent midline epithelial seam in the pups. Through microarray analysis, we detected that 6232 genes were up-regulated and 6310 genes were down-regulated in nicotine-treated groups compared to the control. Moreover, 46% of the cleft palate-causing genes were found to be affected by nicotine exposure. Alterations of a subset of differentially expressed genes were illustrated with hierarchal clustering and a series of formal pathway analyses were performed using the bioinformatics tools. Conclusions: We concluded that nicotine exposure during pregnancy interferes with normal growth and development of the fetus, as well results in persistent midline epithelial seam with type B and C patterns of palatal fusion. Implications: Although there are several studies analyzing the genetic and environmental causes of palatal deformities, this study primarily shows the morphological and large-scale genomic outcomes of gestational nicotine exposure in neonatal mice palate.

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“…46) These TGF-β signaling pathways are crucially involved in the development and maintenance of various tissues, including vessels and craniofacial growth and patterning. Thus, mutations in Tgfbr1 and Tgfbr2 in mice caused craniofacial deformities such as cleft palate, 47,48) and craniofacial manifestations seen in LDS patients may reflect altered TGF-β signaling in neural crest derivatives. 49) Most mutations of TGFBR1 and TGFBR2 genes are missense substitutions of evolutionarily conserved residues that encode serine/threonine kinases, and have been verified in vitro and/or predicted to be associated with loss-of-function (LOF).…”

Section: Loeys-dietz Syndrome (Lds)mentioning

confidence: 99%

Pathophysiology and Management of Cardiovascular Manifestations in Marfan and Loeys–Dietz Syndromes

et al. 2016

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SummaryMarfan syndrome (MFS) is an autosomal dominant heritable disorder of connective tissue that affects the cardiovascular, skeletal, ocular, pulmonary, and nervous systems and is usually caused by mutations in the FBN1 gene, which encodes fibrillin-1. MFS is traditionally considered to result from the structural weakness of connective tissue. However, recent investigations on molecular mechanisms indicate that increased transforming growth factor-β (TGF-β) activity plays a crucial role in the pathogenesis of MFS and related disorders, such as Loeys-Dietz syndrome (LDS), which is caused by mutation in TGF-β signaling-related genes. In addition, recent studies show that angiotensin II type 1 receptor (AT1R) signaling enhances cardiovascular pathologies in MFS, and the angiotensin II receptor blocker losartan has the potential to inhibit aortic aneurysm formation. However, the relationship between TGF-β and AT1R signaling pathways remains poorly characterized. In this review, we discuss the recent studies on the molecular mechanisms underlying cardiovascular manifestations of MFS and LDS and the ensuing strategies for management. (Int Heart J 2016; 57: 271-277)

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Epithelial and ectomesenchymal role of the type I TGF-β receptor ALK5 during facial morphogenesis and palatal fusion

Cited by 137 publications

References 95 publications

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

Nicotine Exposure During Pregnancy Results in Persistent Midline Epithelial Seam With Improper Palatal Fusion

Pathophysiology and Management of Cardiovascular Manifestations in Marfan and Loeys–Dietz Syndromes

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