Type 1 Fibroblast Growth Factor Receptor in Cranial Neural Crest Cell-derived Mesenchyme Is Required for Palatogenesis

Wang, Cong; Chang, Julia Yu Fong; Yang, Chao; Huang, Yanqing; Liu, Junchen; Peng, You; McKeehan, Wallace L.; Wang, Fen; Li, Xiaokun

doi:10.1074/jbc.m113.463620

Cited by 62 publications

(68 citation statements)

References 50 publications

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“…Additionally, conditional inactivation of Fgf8 in the ectoderm of the first pharyngeal arch or Mapk1 and Mapk3 in the neural crest-derived mesenchyme produces similar phenotypes, characterized by agenesis of the maxillary and mandibular prominences and clefting of the nasal prominences (Trumpp et al 1999;Newbern et al 2008;Griffin et al 2013). Conditional inactivation of Fgfr1 in the neural crest-derived mesenchyme produced a milder phenotype of midline facial clefting and normal development of the mandible (Trokovic et al 2003;Wang et al 2013;Brewer et al 2015). Combined deletion of Fgfr1 and Fgfr2 in neural crest cells did produce a more severe facial cleft, although these mutants still fail to recapitulate the facial agenesis caused by conditional loss of Fgf8 (Park et al 2008).…”

Section: Fgf8-erk1/2 Is Required For Development Of the Facial Prominmentioning

confidence: 99%

Genetic insights into the mechanisms of Fgf signaling

2016

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The fibroblast growth factor (Fgf) family of ligands and receptor tyrosine kinases is required throughout embryonic and postnatal development and also regulates multiple homeostatic functions in the adult. Aberrant Fgf signaling causes many congenital disorders and underlies multiple forms of cancer. Understanding the mechanisms that govern Fgf signaling is therefore important to appreciate many aspects of Fgf biology and disease. Here we review the mechanisms of Fgf signaling by focusing on genetic strategies that enable in vivo analysis. These studies support an important role for Erk1/2 as a mediator of Fgf signaling in many biological processes but have also provided strong evidence for additional signaling pathways in transmitting Fgf signaling in vivo.

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Section: Fgf8-erk1/2 Is Required For Development Of the Facial Prominmentioning

confidence: 99%

Genetic insights into the mechanisms of Fgf signaling

2016

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“…Sox11 has been found to regulate Fgf9 in the epithelium of the palatal shelf and receptor Fgfr2 (36) in the nasal side mesenchyme of the palatal shelf. Fgfr-mediated control of cell proliferation has previously been recognized in the lift movement of palatal shelves (53). Ablation of Fgfr1 in the ectomesenchyme results in a cell proliferation delay and cleft palate by impeding palatal shelf elevation prior to shelf fusion (53).…”

Section: Discussionmentioning

confidence: 99%

“…Fgfr-mediated control of cell proliferation has previously been recognized in the lift movement of palatal shelves (53). Ablation of Fgfr1 in the ectomesenchyme results in a cell proliferation delay and cleft palate by impeding palatal shelf elevation prior to shelf fusion (53). However, in contrast to the clefting secondary palate in our Sox11 loss mutation that highlights the extrinsic influence of a malpositioned tongue and micrognathia on the clefting the secondary palate, the cleft palate in loss of function in Fgfr1 is due to the disturbance of cell signaling to delay cell proliferation in both the mesenchyme and epithelium of developing palatal shelves, preventing the shelves from proper elevation and fusion (53).…”

Section: Discussionmentioning

confidence: 99%

“…Ablation of Fgfr1 in the ectomesenchyme results in a cell proliferation delay and cleft palate by impeding palatal shelf elevation prior to shelf fusion (53). However, in contrast to the clefting secondary palate in our Sox11 loss mutation that highlights the extrinsic influence of a malpositioned tongue and micrognathia on the clefting the secondary palate, the cleft palate in loss of function in Fgfr1 is due to the disturbance of cell signaling to delay cell proliferation in both the mesenchyme and epithelium of developing palatal shelves, preventing the shelves from proper elevation and fusion (53). Moreover, Fgf9 associated with Pitx2 has been identified to mediate TGF-␤ signaling and regulate cell proliferation in the palatal mesenchyme during mouse palatogenesis (35).…”

Section: Discussionmentioning

confidence: 99%

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Ablation of the Sox11 Gene Results in Clefting of the Secondary Palate Resembling the Pierre Robin Sequence

Huang

Xiao

Bao

et al. 2016

Journal of Biological Chemistry

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Mouse gene inactivation has shown that the transcription factor Sox11 is required for mouse palatogenesis. However, whether Sox11 is primarily involved in the regulation of palatogenesis still remains elusive. In this study, we explored the role of Sox11 in palatogenesis by analyzing the developmental mechanism in cleft palate formation in mutants deficient in Sox11. Sox11 is expressed both in the developing palatal shelf and in the surrounding structures, including the mandible. We found that cleft palate occurs only in the mutant in which Sox11 is directly deleted. As in the wild type, the palatal shelves in the Sox11 mutant undergo outgrowth in a downward direction and exhibit potential for fusion and elevation. However, mutant palatal shelves encounter clefting, which is associated with a malpositioned tongue that results in physical obstruction of palatal shelf elevation at embryonic day 14.5 (E14.5). We found that loss of Sox11 led to reduced cell proliferation in the developing mandibular mesenchyme via Cyclin D1, leading to mandibular hypoplasia, which blocks tongue descent. Extensive analyses of gene expression in Sox11 deficiency identified FGF9 as a potential candidate target of Sox11 in the modulation of cell proliferation both in the mandible and the palatal shelf between E12.5 and E13.5. Finally we show, using in vitro assays, that Sox11 directly regulates the expression of Fgf9 and that application of FGF9 protein to Sox11-deficient palatal shelves restores the rate of BrdU incorporation. Taken together, the palate defects presented in the Sox11 loss mutant mimic the clefting in the Pierre Robin sequence in humans.

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“…For example, in humans, gain-of-function mutations in FGFR2 and FGFR3 have been consistently observed in individuals with Crouzon syndrome-a genetic disorder that includes craniosynostosis in its list of defects associated with the syndrome. More relevant here, however, is that a KO mouse model in which the Fgfr1 receptors are missing in the cranial neural crest (CNC) cells directly results in CLP due to failures in the proliferation and migration of said cells [14]. Likewise, research has shown that ectopic activation of Fgf8 results in increased proliferation and a failure of the palatal shelves to elevate properly [15].…”

Section: Fgf Signaling Pathwaymentioning

confidence: 99%

A Review of Orofacial Clefting and Current Genetic Mouse Models

Keteyian¹,

Mishina²

2017

Designing Strategies for Cleft Lip and Palate Care

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The prevalence of orofacial clefts (OFCs) is nearly 10.2 per 10,000 births in the United States and 9.9 per 10,000 births worldwide. OFCs occur as a result of a break (nonfusion) of orofacial structures during development. This can occur due to a variety of reasons;prenatal exposure to many drugs and environmental factors as well as genetic factors which are implicated in the development of OFCs. While approximately 15 types of clefts have been identified, there are at least four distinct classifications of OFCs. These include complete cleft palate with cleft lip; cleft of the anterior palate, which may/may not involve cleft lip; cleft of the posterior palate; and submucosal cleft. A number of candidate genes have been identified, including transforming growth factor beta (TGFβ) and homeobox genes (e.g., MSX1), among many others. What follows is a review of mouse models currently used in research and the classification of their overall contribution to known OFCs.

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Type 1 Fibroblast Growth Factor Receptor in Cranial Neural Crest Cell-derived Mesenchyme Is Required for Palatogenesis

Cited by 62 publications

References 50 publications

Genetic insights into the mechanisms of Fgf signaling

Genetic insights into the mechanisms of Fgf signaling

Ablation of the Sox11 Gene Results in Clefting of the Secondary Palate Resembling the Pierre Robin Sequence

A Review of Orofacial Clefting and Current Genetic Mouse Models

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