A specific requirement for PDGF-C in palate formation and PDGFR-α signaling

Ding, Hao; Wu, Xiaoli; Boström, Hans; Kim, Injune; Wong, Nicole; Tsoi, Bonny; O'Rourke, Meredith P.; Koh, Gou Young; Soriano, Philippe; Betsholtz, Christer; Hart, Thomas C.; Marazita, Mary L.; Field, L. Leigh; Tam, Patrick; Nagy, András

doi:10.1038/ng1415

Cited by 203 publications

(231 citation statements)

References 29 publications

(23 reference statements)

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“…Mice lacking Egfr exhibit a low penetrance of CLP (Miettinen et al, 1999), whereas the TGF␣ locus has been associated with nonsyndromic CLP in some human populations (reviewed in Schutte and Murray, 1999;Cobourne, 2004). Mice carrying a null mutation in Pdgfr␣ and mice homozygous for mutations in both the Pdgfr␣ and Pdgfc genes have a median cleft (Soriano, 1997;Ding et al, 2004). Pdgfr function is apparently autonomous to the neural crest, because conditional disruption of Pdgf␣ in neural-crest cells results in a similar facial cleft (Tallquist et al, 2003).…”

Section: Other Genes and Pathwaysmentioning

confidence: 99%

Development of the upper lip: Morphogenetic and molecular mechanisms

Jiang

Bush

Lidral

2005

Developmental Dynamics

277

304

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The vertebrate upper lip forms from initially freely projecting maxillary, medial nasal, and lateral nasal prominences at the rostral and lateral boundaries of the primitive oral cavity. These facial prominences arise during early embryogenesis from ventrally migrating neural crest cells in combination with the head ectoderm and mesoderm and undergo directed growth and expansion around the nasal pits to actively fuse with each other. Initial fusion is between lateral and medial nasal processes and is followed by fusion between maxillary and medial nasal processes. Fusion between these prominences involves active epithelial filopodial and adhering interactions as well as programmed cell death. Slight defects in growth and patterning of the facial mesenchyme or epithelial fusion result in cleft lip with or without cleft palate, the most common and disfiguring craniofacial birth defect. Recent studies of craniofacial development in animal models have identified components of several major signaling pathways, including Bmp, Fgf, Shh, and Wnt signaling, that are critical for proper midfacial morphogenesis and/or lip fusion. There is also accumulating evidence that these signaling pathways cross-regulate genetically as well as crosstalk intracellularly to control cell proliferation and tissue patterning. This review will summarize the current understanding of the basic morphogenetic processes and molecular mechanisms underlying upper lip development and discuss the complex interactions of the various signaling pathways and challenges for understanding cleft lip pathogenesis.

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Section: Other Genes and Pathwaysmentioning

confidence: 99%

Development of the upper lip: Morphogenetic and molecular mechanisms

Jiang

Bush

Lidral

2005

Developmental Dynamics

277

304

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“…The chick, therefore, has the advantage of mirroring the pathology seen in cleft palate, whereas the mouse provides an excellent model to study palatal shelf fusion. Indeed, studies in these animal models have helped to identify a battery of genes essential for palatal formation: Tgfb3 [44]; Bmps [45]; Tbx22 [46]; Fgfrs [47]; Pdgfc [48]; RhoA [49]; the gene encoding PtdIns-3 kinase [43]; Gabrb3 [50]; Gad1 [51,52]; Cspg [53]; and Mmps and Timp2 [54].…”

Section: Animal Models and Expression Datamentioning

confidence: 99%

Orofacial clefting: recent insights into a complex trait

Jugessur

Murray

2005

Current Opinion in Genetics & Development

190

168

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Orofacial clefts are common birth defects of multifactorial etiology. Several novel approaches have recently been applied to investigate the causes of clefts. These include examining Mendelian forms of clefting to identify genes that might also be implicated in isolated clefting, analyzing chromosomal rearrangements in which clefting is part of the resultant phenotype, studying animal models in which clefts arise either spontaneously or as a result of mutagenesis experiments, exploring how expression patterns correlate with gene function and examining the effects of gene-environment interactions. Together, these complementary strategies are providing researchers with new clues as to what mechanisms underlie orofacial clefting.

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“…This facial phenotype is fully recapitulated in mice doubly mutant for Pdgfa and Pdgfc 15. Most Pdgfc mutants have cleft palate 15 MicroRNAs (miRNAs) provide a unique mechanism for modulating signaling pathways [17][18][19][20] . Skeletogenic, including palatal, precursors express mirn140 (miR-140) in teleosts 21 and amniotes [22][23][24] , suggesting that Mirn140 may modulate signaling during palatogenesis across vertebrate species.…”

Section: Introductionmentioning

confidence: 99%

“…4a,c,e,g). This expression pattern suggests that Pdgfra mediates migration of palatal precursors to the oral ectoderm.To determine what ligand Pdgfra utilizes during crest cell migration, we cloned and surveyed the expression of the zebrafish homologues of Pdgfa and Pdgfc, because mice doubly mutant for these genes recapitulate the mouse Pdgfra mutant phenotype 12,15 . The zebrafish genome (http://www.ensembl.org/Danio_rerio/index.html) contains a single copy of pdgfc and duplicates of pdgfa, we designate these pdgfaa (formerly called pdgf-a 29 ) and pdgfab.…”

mentioning

confidence: 99%

MicroRNA Mirn140 modulates Pdgf signaling during palatogenesis

et al. 2008

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Disruption of signaling pathways such as those mediated by Shh or Pdgf causes craniofacial disease, including cleft palate. The role that microRNAs play in modulating palatogenesis, however, is completely unknown. We show, in zebrafish, that the microRNA Mirn140 negatively regulates Pdgf signaling during palatal development and we provide a mechanism for how disruption of Pdgf signaling causes palatal clefting. The pdgf-receptor alpha (pdgfra) 3' UTR contains a Mirn140 binding site functioning in the negative regulation of Pdgfra protein levels in vivo. Both pdgfra mutants and Mirn140-injected embryos share panoply of facial defects including clefting of the crestderived cartilages that develop in the roof of the larval mouth. Concomitantly, the oral ectoderm beneath where these cartilages develop loses pitx2 and shha expression. Mirn140 modulates Pdgfmediated attraction of cranial neural crest cells to the oral ectoderm, where crest-derived signals are necessary for oral ectodermal gene expression. Both Mirn140 loss-of-function and pdgfra overexpression alters palatal shape and causes neural crest cells to accumulate around the optic stalk, a source of the ligand Pdgfaa. Conserved molecular genetics and expression patterns of mirn140 and pdgfra suggest that their regulatory interactions are ancient methods of palatogenesis that provide a candidate mechanism for cleft palate.Cleft palate and other craniofacial diseases are common in humans and have complex cellular and genetic etiologies. In amniotes, the palate serves to separate the nasal and oral cavities and is generated through an intricate series of morphogenic events that include early neural crest cell migration and cell-cell signaling during the formation of facial prominences, as well as later generation and fusion of palatal shelves. While later events involving palatal shelves have not been described in zebrafish, palatal precursors migrate both rostral and caudal to the eye to condense upon the oral ectoderm in amniotes 1 as well as zebrafish 2,3 and evidence continues to accumulate that the early signaling environment governing palatogenesis is also largely equivalent [3][4][5][6] . For instance, Hh signaling is crucial for palatogenesis in humans and zebrafish 3,4,7 . Zebrafish and amniotes also share expression patterns of palatogenic genes such as Shh 4,8 , Fgf8 4,9,10 and Pdgf receptor alpha (Pdgfra) [11][12][13] .In mouse, the Pdgf family consists of four soluble ligands, Pdgfa, Pdgfb, Pdgfc, and Pdgfd as well as two receptor tyrosine kinases, Pdgfra and Pdgfrb 14 . Pdgf signaling regulates a myriad of biological processes as demonstrated by analyses of mouse Pdgf ligand and receptor mutants 14 . Mice null for Pdgfra have a facial clefting phenotype that includes cleft palate 12,13 . This facial phenotype is fully recapitulated in mice doubly mutant for Pdgfa and Pdgfc 15. Most Pdgfc mutants have cleft palate 15 MicroRNAs (miRNAs) provide a unique mechanism for modulating signaling pathways [17][18][19][20] . Skeletogenic, including...

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A specific requirement for PDGF-C in palate formation and PDGFR-α signaling

Cited by 203 publications

References 29 publications

Development of the upper lip: Morphogenetic and molecular mechanisms

Development of the upper lip: Morphogenetic and molecular mechanisms

Orofacial clefting: recent insights into a complex trait

MicroRNA Mirn140 modulates Pdgf signaling during palatogenesis

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