2016 Group Project 3

From Embryology
2016 Student Projects 
Signalling: Group 1 | Group 2 | Group 3 | Group 4 | Group 5 | Group 6
2016 Group Project Topic - Signaling in Development

OK you are now in a group, add a topic with your student signature to the group page.

This page is an undergraduate science embryology student project and may contain inaccuracies in either descriptions or acknowledgements.
Group Assessment Criteria 
Mark Hill.jpg Science Student Projects
  1. The key points relating to the topic that your group allocated are clearly described.
  2. The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.
  3. Content is correctly cited and referenced.
  4. The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.
  5. Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.
  6. Relates the topic and content of the Wiki entry to learning aims of embryology.
  7. Clearly reflects on editing/feedback from group peers and articulates how the Wiki could be improved (or not) based on peer comments/feedback. Demonstrates an ability to review own work when criticised in an open edited wiki format. Reflects on what was learned from the process of editing a peer's wiki.
  8. Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement.
  9. The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic and covered the key areas necessary to inform your peers in their learning.
  10. Develops and edits the wiki entries in accordance with the above guidelines.
More Information on Assessment Criteria | Science Student Projects

Fibroblast Growth Factor Receptor (FGFR) Pathway

Introduction

The Fibroblast Growth Factor (FGF) signalling pathway is critical for regulating progenitor cell proliferation, differentiation, survival and patterning. It is involved in the regulation and development of the early embryo, and is considered to be critical for normal vascular, skeletal and organ development. Furthermore, this pathway is involved in maintaining adult tissues through the regulation of metabolic functions and tissue repair (which is often through the reactivation of the same signalling pathways involved in early development.) [1]

This page will outline the FGFR signalling pathway, the history of scientific discoveries relevant to this pathway, receptor sub-types and a description of signal transduction. It will also describe its various roles in embryonic development including its influence on the patterning of the embryonic axis, as well as limb bud, bone, kidney, external genitalia and inner ear development. There is also a discussion of relevant animals models, such as those of the chick embryo, as well as abnormalities in this pathway relevant to embryonic development, including Achondroplasia, Pfeiffer syndrome and Apert syndrome. A short informative quiz accompanied with feedback is offered for readers to determine how much they have learnt from the information provided. A glossary at the bottom of the page explains specific terms mentioned throughout, along with links to relevant information from UNSW embryology lectures.

History

Ranging from its discovery in 1939 till the present, much has been learned about the nature of Fibroblast growth factor (FGF) in embryonic development. Researchers had noticed the growth stimulating effects that these isolated factors had, in that they induced fibroblast proliferation. Due to their ability to stimulate fibroblast proliferation they were termed "FGFs". Today, a variety of subtypes of FGFs have been discovered and categorised into a large family that exist in organisms including humans as well as nematodes. In addition, it was soon discovered that not all FGFs can stimulate fibroblasts.

The table below outlines some of the significant scientific discoveries regarding the FGFR signalling pathway over the years, as outlined in a review article. [2]

Year Scientific Discovery Regarding FGF/FGFR Signalling
1939 The first paper on FGFs was published through experiments that measured the mitogenic activity of saline extracts of different tissues from the chick. Early work also investigated the idea that uncontrolled proliferation is a hallmark of cancers and the involvement of growth factors such as FGF.
1974 FGF growth factor activity was shown to stimulate the growth of a fibroblast cell line in partially purified extracts from bovine pituitary. This lead to the term "fibroblast growth factor" to be derived.
1987 The interaction with heparin that FGFs have was translated into work regarding the interaction of FGFs with the glycosaminoglycan heparan sulfate within the pericellular and extracellular matrix.
1989 FGF1 and FGF2 were isolated from brain tissue.
1990 FGFR tyrosine kinases were identified for the first time
1991 FGFs were also shown to display growth factor activities on fibroblasts. In addition, the dependence of the growth factor activity of FGFs on heparan sulfate was discovered.
2005 A further set of FGF proteins termed the FGF homology factors were found to be wholly intracellular such that they do not interact with any of the extracellular receptors and partners of FGFs.
2013 A small group of FGFs were found to not bind heparan sulfate, but instead to interact with a protein co-receptor named Klotho.

Overview Of The FGFR Pathway

23 protein families have been identified from the FGF signalling pathway, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) that interact with 4 tyrosine kinase FGF Receptors (FGFR1-4), whilst 4 are intracellular non-signalling proteins (iFGFs; FGF11-14). [1]

As illustrated in the image below, FGFRs are comprised of 3 immunoglobulin domains (IgI, IgII, IgIII), with IgIII being the closest to the transmembrane and IgI being the furthest away. Some notable features of this receptor include an acidic box (AD) located in-between IgI and IgII, a heparin-binding domain (HBD) within IgII which is important in signal transduction, and the transmembrane (TM) structure of IgIII which has both kinase and interkinase domains (KD and IKD) within the intracellular space. FGF ligands linked to heparin sulfate proteoglycan (HSPG) bind to both the IgII and IgIII domain of the receptor (with the heparin component specifically binding to IgII) resulting in dimerisation of the receptors and activation of signal transduction pathways through the phosphorylation of tyrosine residues, as discussed in more detail under the subheading signal transduction. [3]


Simplistic illustration of the FGFR receptors adapted from review article Functions and regulations of fibroblast growth factor signaling during embryonic development

Subtypes of FGFR

FGFR Subtype Function Abnormalities
FGFR1
  • Involved in morphogenesis as well as orchestrating the patterning of the mesodermal germ layer at gastrulation[4]
  • Involved in formation of the organ of corti and auditory sensory epithelium [5]
  • Expressed in early limb bud [6]

  • Expressed at epiphyseal growth plate as well as in the perichondrium, prehypertrophic and hypertrophic chondrocytes[7]
  • Is a negative regulator of bone growth[8]
  • Pfeiffer Syndrome (Type 1)
  • Kallmann syndrome
  • Osteoglophonic dysplasia
  • 8p11 myeloproliferative syndrome
FGFR2
  • Activated prior to gastrulation with the purpose of repressing cellular movements in the presumptive anterior neural plate and preventing normal retinal progenitor cells from adopting retinal fates[9]
  • Acts as a marker of prechondrogenic condensations[10]
  • Expressed in condensing mesenchyme of the early limb bud[11]
  • Plays a key role in skeleton development as it is expressed in osteoprogenitor cells and differentiating osteoblasts[12]
  • Is involved in cranial cell replication or differentiation in both humans and mice.[13]
  • Pfeiffer Syndrome (Type 1-3)
  • Apert Syndrome
  • Crouzon Syndrome
  • Beare-Stevenson cutis gryata syndrome[14]
FGFR3
  • Induces complete growth arrest of cells[15]
  • Is required to promote differentiation of prechondrogenic mesenchymal cells to cartilage-producing chondrocytes [16]
  • Is expressed in chondrocytes, differentiated initially from the core of the mesenchyme condensation[17]
  • Is expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed[18]
  • Achondroplasia (can be severe, with developmental delay and acanthuses)
  • Thanatophoric Dysplasia
  • Hypochondroplasia
FGFR4
  • Involved in proliferation of the blastocyst inner cell mass, differentiation of the presomitic mesoderm and limb bud development[19]
  • Regulates cholesterol metabolism, bile acid synthesis and liver mineral homeostasis
  • It will provide mitogenic and morphogenic signals to regulate normal limb development[18]
  • Promotes intramembranous ossification and participates in the development of calvarial bone[19]
  • Chondrodysplasia

Signal Transduction


FGFR Signalling Pathway (Image based upon[20])

The process of signal transduction commences with the binding of a cognate ligand to FGFRs ligand binding site which in turn triggers receptor dimerization. This dimerization of the receptor will cause activation of intrinsic kinase activity[21]. This will activate multiple signal transduction pathways intracellularly including RAS, Mitogen-activated protein kinase (MAPK), p38 MAPKs, Phospholipase-C-Gamma, Crk, Protein Kinase-C and Phospholipase-C-Gamma and Extracellular signal-regulated kinases. Activation of FGFRs induces tyrosine phosphorylation of FRS2 (FGFR stimulated2 Grb2 binding protein) which in turn stimulates the recruitment of GRB2 (Growth factor receptor bound protein-2) and SHP2 ( Src homology 2 phosphatase-2) [22].

In turn, this sequence of events promotes sustained activation of RAS, which leads to changes in gene transcription through interactions with DNA. In addition, FGF receptors will also induce the activation of PI3K (phosphatidylinositol-3-Kinase), STAT1 and Src tyrosine kinase, which will contribute to certain FGF-stimulated biological responses [23].

With respect to embryonic development, both the PI3K and RAS pathways are essential in order for the normal mesoderm to develop in the embryo. Additionally, receptor-mediated induction of the SHP2-RAS-ERK pathway is a key mechanism through which FGF can activate a variety of biological signalling pathways including cell growth, cellular differentiation as well as morphogenesis [24].

YouTube video outlining FGF Signalling Pathway


This is a YouTube animation which illustrates a simplified version of the FGF Signalling pathway discussed above. This signalling pathway leads to changes to gene expression that, for example, can result in changes in cell growth, division or differentiation.[25]

Role In Embryonic Development

Patterning Of The Embryonic Axis

In the process of patterning of the embryonic axis, the caudal primordium that is part of the neural plate, contains cells that are rapidly dividing and is able to maintain itself as a growth region (this region is considered to be of "stem cell" status). The expanding populations of dividing cells spread along the neural tube by cell movements of convergence and extension. As cells undergo a process whereby they are driven out of the tube, they change their pattern of movement, which eventually causes a gradual restriction in space[26]. Within this process, it is the misexpression of a dominant negative FGFR construct in the tissue which causes these cells to prematurely leave the stem cell region and to change their movement patterns as if they had aged[27].


Furthermore, Mathias et al. (2001) suggest that FGFR is required in order to maintain this stem cell status in the caudal neural plate during patterning of the nervous system. In addition, it is possible that FGF serves the purpose of acting as a caudalizing factor for the neural tube because it is capable of prolonging the window of time during which cells are exposed to a caudalizing factor.

In summary, FGF signalling is important in regulating the maturation of developing cells which are gradually being laid down in a caudal direction along the axis of the neural tube.

Limb Bud Formation

Mechanisms of FGF signalling during organises; a-c: limb development, d-e: lung development, f-h: induction of the otic placode and differentiation of the otic vesicle[1]

Limb buds are structures formed early in limb development which are comprised of lateral plate mesoderm (LPM) cells and an overlying surface ectoderm. They are roughly formed around week 4 of embryonic development as a result of interactions between the mesoderm and ectoderm germ layers.

FGF proteins and its interactions with other signalling pathways, are critical for the initiation and proximal-distal growth of limbs from a limb bud structure.[28] The following information is accompanied by a YouTube video below and the image on the right, where figures a-c corresponds specifically to limb bud formation[1] Prior to limb bud formation, FGF10 is widely expressed in the LPM and is stabilized by the WNT signaling proteins. FGF10 is responsible for stimulating the expression of WNT3 (and downstream transcription factors including SP6 and SP8[29]) in the overlying ectoderm, which results in the formation of the Apical Ectodermal Ridge (AER), a specialised thickening of epithelium located towards the proximal end of the bud that is required for growth,[1] which subsequently stimulates FGF8. FGF8 is responsible for continued growth of the underlying mesoderm by keeping it in a mitotically active state, and stimulating a positive feedback loop on FGF10 (which in turn stimulates increased FGF8 expression). FGF8 is the known AER-specific FGF to be expressed throughout it, although other FGFs are expressed in the posterior AER (including Fgf4, Fgf9 and Fgf17) and are thought to have supporting roles.[30][31] FGFs in the AER signal FGFR1 and FGR2 in distal mesenchyme, activating ETV1 and EWSR1 which function to help to maintain FGF10 expression.[32]

Furthermore, the Zone of Polarising Activity (ZPA) is a region located on the posterior side of the limb bud composed of mesenchyme which signals its anterior-posterior growth (for example this region signals the position of the thumb relative to the little finger.) The Fibroblast Growth Factors FGF2[33], FGF4[34] and FGF8[35] induce Sonic Hedgehog (SHH) within ZPA region and is critical for its growth along the anterior-posterior axis.

Therefore together these interactions of the FGFs from the AER help to maintain proliferating cells near the distal tip of the limb bud, and are known to be critical in limb bud development, both along the proximal-distal axis and the anterior-posterior axis. It is also important to note that growth along the dorsal-vental axis is dependent on the involvement of growth factors from the Wnt family on the ectodermal layer.

FGF signaling is also involved in lung bud initiation and development, with a similar underlying process.This is supported by the accompanying image on the right, where figures d and e specifically looks at the interplay of FGFs and FGFRs on the lung bud imitation and lung development.[1]


YouTube video outlining limb bud development


YouTube video outlining limb bud development[36]

Bone Development

FGF and FGFR expression patterns during endochondral and intramembranous bone development [37]

Much of what we now understand about the involvement of the FGF signalling pathway in bone development is a result of discovering missense mutations responsible for conditions characterised by abnormal bone structure, including but are not limited to, skeletal dysplasias and craniosysnostosis syndromes (some of which discussed in more detail later under the subheading abnormalities.) The first and questionably the most important mutation discovered affecting skeletal development was a point mutation of the FGFR3 protein, which was found to be responsible for achondroplasia. [38]

FGF signalling is involved in both endochondral and intramembranous bone development, which are critical in the early stages of embryonic bone formation. As shown in the diagram to the right the presence of FGFR1-3 and FGF2, FGF9, FGF18 are involved in various stages of bone development.

Endochondral bone development (A-D in the figure) is responsible for forming the long bones of the appendicular skeleton, face and spinal column. This involves an intermediate cartilage template (which helps control the growth and patterning of the development of the bony structure.) As shown in the figure provided by a review article[37] FGFR signalling is present across different stages of development (ranging from mesenchymal condensation to the establishment of the primary ossification centre. FGFR2 (light blue) expression is prominent in mesenchymal condensation, FGFR1 (white) is uniformly expressed throughout the mesenchyme, and both FGFR3 (red) and FGFR4 (not shown) are not present in distal limb bud mesenchyme and expressed proximally in tissues related to developing muscle. [39] In comparison, intramembranous bone development (G in the figure) is responsible for forming bones of the skull and clavicles, and doesn’t require a cartilage template, it directly forms bone. As shown in the figure provided by a review article[37] we primarily see the presence of FGFR1 (white) on mesenchymal cells and both FGFR1 and FGFR2 (dark blue) on osteoprogenitor cells, osteoblasts and osteocytes (in mineralised bone.) Furthermore, this figure also shows FGF and FGFRs involvement in both the Embryonic (E in the figure) and Postnatal Growth Plate (F in the figure) and highlights how they are distributed differently between these two stages of life.[37]

For additional information see the recent (2015) review article by Ornitz1 and Pierre Fibroblast growth factor signaling in skeletal development and disease

Kidney Development

The metanephric kidney is an organ which arises primarily form two tissues, the nephrogenic cord and the Wolffian duct, which will eventually give rise to the metanephric mesenchyme and the ureteric bud respectively [40]. Around week 5 of gestation in the developing human embryo, the metanephric mesenchyme will release signalling molecules that stimulate the ureteric bud to grow out from the Wolffian duct and invade the metanephric mesenchyme. The stromal mesenchyme that exists between the Wolffian duct and the metanephric mesenchyme restricts the ureteric bud to its proper position and prevents ectopic budding[41]. The metanephric mesenchyme will continue to release signals which will stimulate the ureteric bud to elongate and repeatedly branch, leading to formation of the ureter, collecting duct system and the renal pelvis. Following its contact with the ureteric bud, the metanephric mesenchyme will then divide into a nephrogenic lineage lying adjacent to the bud, and a surrounding renal cortical stromal lineage [42]. Each terminal tip of the ureteric bud induces local areas of nephrogenic mesenchyme in order to differentiate into nephron epithelia, progressing from renal vesicles ,to comma-shaped bodies, to S-shaped bodies, and then to immature nephrons[42]. The renal cortical stroma will provide a framework and likely a niche for the other renal lineages and vasculature, and ultimately differentiates into interstitial and other supportive cells within the kidney [43].

In terms of the development of the metanephric kidney, all FGFRs have been detected in the process of development, however studies using animal models have revealed that it is FGFR1, FGFR2 and FGFR11 which play a key role in renal development [44]. FGFR1 is a receptor which is expressed mostly in the metanephric mesenchyme lineages, these including the early metanephric mesenchyme, the cap mesenchyme and the developing nephrons beginning with vesicles. However, FGFR1 is present at lower levels in the ureteric lineage and in the renal cortical stroma[45]. In contrast, FGFR2 is strongly expressed in the Wolffian duct and the ureteric bud tree as well as the differentiating nephrons. Despite this, FGFR2 is present at lower levels in the early metanephric mesenchyme and stomal mesenchyme adjacent to the Wolffian duct[46]. In addition, FGFR11 is present in renal vesicles [46].

External Genitalia development

External genitalia development[47]

The genital tubercle (GT) is a structure from which characteristics in the external genitalia in the adult develop. The GT differentiates into a penis in males and a clitoris in females. The process of proximodistal elongation of this GT involves multiple interactions between growth factors and transcription factors [48]. Interactions between epithelium and mesenchyme have an essential role in the regulation of various development processes throughout the embryo. Such signalling controls many aspects of organogenesis, from the initiation of organ development to differentiation [49].

The FGFR signalling pathway is involved in epithelial to mesenchymal interactions during organogenesis. Studies have revealed that the first morphological sign of GT outgrowth occurs at approximately 10.5 days post coitum, and will continue throughout the perinatal period [50]. Initially within the developing embryo, the external genitalia of the male and female foetuses are morphologically identical and consist of the GT. Several growth factors including FGF proteins have been shown to control external genitalia development in mice [51]. FGF8, FGF10 and FGFR2 expression has been found during GT developing, thus suggesting that a combination of these factors may constitute redundant developmental functions during GT morphogenesis[52]. As the GT elongates, a groove appears on its ventral aspect called the urethral groove. At the distal end, this groove is made up of a solid plate of epithelial cells, the distal urethral epithelium (DUE) that extends into the glans penis. The solid urethral plate canalizes and thus extends the urethral groove distally into the glans. It was found that FGFR2IIIb is expressed in the DUE and urethral plate epithelia of the GT. Deletion of this receptor and FGF10 was shown to cause urethral dysmorphogenesis.

It was also shown that the deletion of FGR2 or FGF10 would result in hypospadias in mice, where when FGFR2 was deleted in the ectoderm leads to severe hypospadias and absence of the ventral prepuce whereas when FGFR2 was deleted in the endoderm, mild hyospadias occurs and maturation of complex urethral epithelium was inhibited[53]. Specifically, in female mice, it was shown that those mice with severe hypospadias had a single urogenital opening and in a particular group of these mice, the tip of the urethral plate was separated from the vaginal orifice. These results indicates that FGFR2 action mediates urethral epithelial maturation and FGFR2 in the ectoderm is responsible for the formation of prepuce.

Inner Ear Development

File:Inner ear development.jpg
Inner ear development (Image was retrieved from a review article[54]

The inner ear, containing the vestibule and cochlea, is derived from a simple ectodermal thickening called the otic placode. Genetic evidence and expression of data has lead to the suggestion that FGF3 and other fibroblast growth factor types influence early development of the mammalian inner ear, specifically by regulating the formation of the endolymphatic duct [55]. FGFR-3 is expressed in the cochlear special sensory epithelium, particularly during late embryogenesis and during postnatal life. To reinforce this, further investigations have revealed that FGFR3 absence leads to deafness attributable to disturbances in the differentiation of the cochlear sensory epithelium[56]. Studies have also revealed that cochlear neuron-derived FGF1 and inner hair cell-derived FGF8 may serve as ligands which bind to FGFR-3 during the late embryonic and postnatal cochlea. In addition, FGF9 mRNA has been localised to the otic vesicle and to the later developing nonsensory epithelium and ganglion of the cochlea[57].

In studies which investigated the dynamic expression patterns of FGF10 and FGFR-2 mRNAs, it was revealed that FGF10 was widely expressed in the undifferentiated otic epithelium however it was subsequently restricted to the presumptive cochlear and vestibular sensory patches. Also, the strong expression of FGF10 mRNAs was found in the otic epithelium-derived neuronal precursors and in the neurons of the cochleovestibular ganglion. Furthermore, te expression of FGF10 mRNA and its colocalization with neurotrophin mRNAs in the ventral patch is indicative that neurons belonging to the inner ear as well as part of the sensory epithelium, have a common origin in this epithelial domain[58]. In the cranial nerve ganglion, FGF10 mRNA was found within those of the cochlear and vestibular ganglia and not in the surrounding ganglia, which is suggestive that FGF10 relates to the unique colocalization of neurotrophin receptors in the inner ear sensory neurons. Alternative studies have revealed that hindbrain-derived FGF3 has been suggested to regulate patterning of the inner ear, particularly the endolymphatic duct [59]. It was further revealed that FGF3 mRNA is expressed in the ventrolateral region of the otic vesicle at the same stage that it is visible in the hindbrain.

Animal Models

Mouse Models

Over the past few decades, extensive studies in mice have yielded insights into the roles of various FGF molecules and signalling pathways in embryonic development. In particular, loss-of-function genetic analysis in the mouse has been crucial for understanding FGF function. [60]

For example, one of the most recent models developed for studying Fgf functions during development, as reported in Genesis in February 2016, is the Fgf3(Δ)-Fgf4(flox)-cis mouse line [60]. This model newly allows exploration of redundancy between Fgf3 and Fgf4 genes which are both located on chromosome 7, 18.5 kb apart, by retargeting Fgf3 and Fgf4 in cis, generating an Fgf3 null allele and a conditional Fgf4 allele subject to Cre inactivation. The line showed caudal axis extension defects in Fgf3 mutants to worsen with Fgf4 inactivation, demonstrating redundancy. The model can be applied in the future study redundancy of these genes in a variety of tissues and stages of development.

The following table summarises selected mouse models with germline, conditional or temporarily induced knockout or deficiency for specific FGFs that have been used to certain demonstrate defective aspects of embryological development. Many of these mouse models continue to be used in emerging medical research into the respective pathologies they characterise.

Animal Models

Mouse Models

Over the past few decades, extensive studies in mice have yielded insights into the roles of various FGF molecules and signalling pathways in embryonic development. In particular, loss-of-function genetic analysis in the mouse has been crucial for understanding FGF function. [60]

For example, one of the most recent models developed for studying Fgf functions during development, as reported in Genesis in February 2016, is the Fgf3(Δ)-Fgf4(flox)-cis mouse line [60]. This model newly allows exploration of redundancy between Fgf3 and Fgf4 genes which are both located on chromosome 7, 18.5 kb apart, by retargeting Fgf3 and Fgf4 in cis, generating an Fgf3 null allele and a conditional Fgf4 allele subject to Cre inactivation. The line showed caudal axis extension defects in Fgf3 mutants to worsen with Fgf4 inactivation, demonstrating redundancy. The model can be applied in the future study redundancy of these genes in a variety of tissues and stages of development.

The following table summarises selected mouse models with germline, conditional or temporarily induced knockout or deficiency for specific FGFs that have been used to certain demonstrate defective aspects of embryological development. Many of these mouse models continue to be used in emerging medical research into the respective pathologies they characterise.

Mouse Type Phenotype expressed Viability in Null Mutant
Fgf1-, Fgf21-
  • impaired energy/lipid metabolism, diabetes under high-fat diet[61]
    [62]

Viable

Fgf2-
  • decreased vascular muscle contractility, low blood pressure, thrombocytosis [63]
  • decreased cardiac hypertrophy in ischaemic injury [64]
  • reduced cortical neurogenesis [65]
  • reduced skin wound healing [65]
  • reduced trabecular bone formation [66], dwarfism, rickets, osteomalacia [67]

Viable

Fgf3-
  • defective inner ear [68]
  • defective heart [69]

E15.5 [69]

Fgf4-
  • impaired blastocyst inner cell mass proliferation [70]

E4-4 [70]

Fgf7-
  • impaired ureteric bud development, decreased number of nephrons [71]
  • prone to seizures [72]

Viable [71]

Fgf8-
  • failed gastrulation [73]
  • defective kidney development [74]
  • defective limb development [75]
  • defective inner ear [76]
  • defective cerebellum [77]
  • defective heart outflow tract [78]

E7 [79]

Fgf9-
  • lung hypoplasia [80]
  • male to female sex reversal [81]
  • rhizomelia [82]
  • shortened small intestine [83]
  • cecal agenesis [84]
  • cardiomyopathy [85]
  • ataxia [86]

P0 [87]

Fgf10-
  • lung hypoplasia [88]
  • defective limb development [88]
  • defective inner ear formation [89]
  • defective pancreatic development [90] submandibular salivary gland [91] and defective mammary gland [92]
  • defective tracheal cartilage [93] and cleft palate [94]
  • cecal agenesis [95]

P0 [88]

Fgf 13-
  • impaired learning memory and neuronal excitability, neuronal migration defects [96]

Viable

Fgf14-
  • impaired learning, memory and neuronal excitability [97]
  • ataxia [98] and motor weakness [97]

Viable

Fgf15-
  • Heart defects in outflow tract [99]
  • neurogenesis [100]
  • bile acid metabolism [101]

E13.5-P7 [102]

Fgf16-
  • cardiomyopathy [85]

Viable

Fgf17-
  • defective cerebellum [103]
    and frontal cortex [104]

Viable

Fgf18-
  • lung development defects [105] [106]
  • bone and cartilage development defects [107]

P0 [105]

Fgf20-

Viable [85]

Fgf23-
  • deafness, defective middle ear development [109]
  • hyperphosphatemia and impaired vitamin D metabolism [110]

PW12 [110]

The Importance of FGF10 in Limb and Lung Development in Chicks and Mice

Mice model and limb development[88]

In vertebrate embryos, initiation of limb buds results from the outward proliferation of the lateral plate mesoderm[111]. The distal ectoderm surrounding this region is then induced by dividing mesenchymal cells to thicken and form a structure called the apical ectodermal ridge (AER). Molecular interactions that occur between the AER and the underlying mesenchyme are vital in order for proximal-distal patterning to occur. FGF2, 4 and 8 are expressed in the AER of Chicks, and are capable of replacing the AER to induce underlying mesenchyme to maintain its distal outgrowth. The anterior-posterior patterning of each limb bud is regulated by the zone of polarizing activity (ZPA), which is located at the posterior margin of the limb bud mesenchyme[112].

Tissue graft experiments have indicated that vertebrate limb bud formation is initiated by factors from mesoderm within the limb field[112]. Implantation of beds soaked in FGFs or FGF-expressing cells is capable of inducing formation of ectopic limbs within chick embryos. FGF 1, 2, 4, 8 and 10 were shown to exhbit limb-inducing activity[113]. However, only FGF8 and FGF10 will express demonstrate the correct temporal and spatial expression that could guide the initiation of the limb bud. FGF8 in chick embryos is expressed in the intermediate mesoderm at presumptive limb regions before limb bud initiation. This is compared to FGF10, which is only expressed in the lateral plate mesoderm within the limb field prior to limb bud initiation, and the expression persists in the mesenchyme under AER after initial limb bud formation[114].

Evidence also suggests that FGF10 may also affect development of the vertebrate lung. In mice, the process of lung morphogenesis begins with ventral extension of the laryngotracheal groove from the primitive gut endoderm approximately at E9.5. After this stage, the tracheal primordium will bifurcate to produce left and right principal bronchi, around which the lung buds differentiate. Further branching of these bronchi result in the development of bronchioles and alveoli that form mature lung parenchyma. A recent study suggests that an FGF-mediated signal plays a major role in lung development. A splice variant of FGFR2 is highly expressed in respiratory epithelium during early branching morphogenesis in the epithelium of the respiratory tract during early branching morphogenesis[115].In further investigations, when FGF10 was absent in the developing embryos of mice, there was complete absence of budding limbs at E9.5 whilst all other external structures remained. Thus these results suggest that FGF10 is necessary for limb bud initiation[88].

Abnormalities

As discussed above, the FGF signalling pathway is critical for regulating many early embryonic developmental processes, and is critical for normal organ, vascular and skeletal development. Consequently, abnormalities in genes coding for the proteins within this signalling pathway (including signalling proteins, non-signalling proteins, and receptors) can result in many visible structural abnormalities such as short statue and face deformations. Not to mention that a large majority of these conditions, if not all, influence an individual’s quality of life, and in some cases increase risk of fatality. Some of these FGF abnormalities are outlined in more detail below, including Achondroplasia, Pfeiffer and Apert Syndrome which particularly emphasise the significance of FGF signalling in early skeletal development.

Achondroplasia

Achondroplasia is the most common form of skeletal dysplasia, and is often characterised by shortened proximal limbs, a curved spine, a large prominent forehead and a fattened nasal bridge. This condition is inherited genetically as an autosomal dominant trait, although a large proportion of cases are sporadic. [116] This condition results in reduced inhibition of endochondral ossification, which is one of the main way in which bone tissue is created during embryonic development (the other being intramembranous ossification.) Endochondral ossification is essential during development for both the formation and growth of long bones as well as healing fractures. For the majority of affected individuals, it is a result of a missense mutation in FGFR3, specifically due to a substitution of arginine for glycine (G380R).[117] As originally postulated by Bonaventure et al. (1996) this introduction of a hydrophilic residue in a hydrophobic receptor domain results in a disruption of alpha-helical structure of the transmembrane portion of the protein and consequently interferes with the signal transduction pathway of which it is involved in. [118]

There are other mutations in FGFR3 which are responsible for different skeletal developmental conditions, including a more severe (usually fatal) form of skeletal dysplasia, Thanatophoric Dysplasia, which is due to two different mutations, K650E and R248C in FGFR3 (type 1 and type 2 respectively) and a milder form, hypochondroplasia, which is due to the mutations, N540K or K650N in FGFR3. Recent studies have also shown expression of an fgf4 retrogene to be associated with achondroplasia in domestic dogs. [119]

Pfeiffer Syndrome

Pfeiffer syndrome is characterised by craniosynostosis, meaning that is it a condition where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. Subsequently, abnormal growth of the skull, in an attempt to increase the space available for the brain and reduce cranial pressure, results in the development of abnormal facial features including, but not limited to, proptosis (abnormal placement of the eye), hypertelorism (abnormal increase in distance between the eyes), maxillary deficiency, and a beaked nose. Other notable features include those of the hands, broad thumbs and the feet, medially deviated broad great toes. [120][121] This condition is inherited genetically as an autosomal dominant trait. There are 3 types of Pfeiffer syndrome. Type 1 is a result of either a gain of function P252R mutation of FGFR1 (5%), which increases the receptor’s ligand binding affinity resulting in over-activation of the receptor, or sequence variants of FGFR2 gene (95%.)[121] Type 2 and 3 are similar, both appear more severe and generally have a worse prognosis compared to Type 1, and are a result of mutations of the FGFR2 gene. [122][123]

YouTube video outlining Pfeiffer Sydrome


YouTube video outlining Pfeiffer Sydrome[124]

Apert Syndrome

Syndactyly of the fingers

Apert syndrome is characterised by craniosynostosis, as well as turribrachycephaly (high, prominent forehead), midface hypoplasia (incomplete/underdevelopment) and syndactyly (cutaneous and bony fusion) of the fingers and toes. This condition is inherited genetically as an autosomal dominant trait. It is a result of a gain-of-function mutation of FGFR2, specifically at S252W or P253R region, which is responsible for increased receptor affinity for the binding ligand and subsequently result in excessive activation of the receptor. [125][121] It is currently thought that the P253R mutation will increase the affinity of FGFR2 to all FGFs, whereas the S252W mutation on the other hand will increase the affinity of FGFR2 only to a selective subset of FGFs. [126] The genotype of the mutation is thought to explain clinical variability in the presentation of the condition in patients. [121]

Cleft Lip and Palate

Regulation of Fgf18 during palatal shelf development

Cleft palate, and cleft lip with or without cleft palate, are distinct but common congenital craniofacial birth defects [127]. Within the human population, isolated cleft palate affects one in every 1,000 births (whereas cleft lip with or without cleft palate has a higher incidence of one in 700 births, whilst 55% of all cases are associated with other abnormalities as part of a syndrome [128]. These defects have a complex and heterogeneous etiology which is not yet fully understood, however mutations in a variety genes have been implicated, including FGF and FGFR-associated genes.

The mammalian secondary palate is formed from bilateral outgrowths of the maxillary processes, which begin to develop in the embryonic day 12 in the mouse and form shelves growing downwards between the developing tongue and lower jaw. They then elevate to a horizontal position above the tongue at E14, and patterning along the mediolateral and anteroposterior axis occurs [129]. Fusion of the shelves together and with the primary palate then forming a barrier between the oral and nasal cavities [130]. From the primitive facial tissue lobes, the frontonasal prominence and maxillar prominence grow to form the upper lip. Abnormalities in any stage of these processes can result in a hole, or ‘cleft’, between the mouth and nose, or in the lip.

Recent studies have investigated the role of FGF signalling in early palate development in mice. Rice et al. found that both Fgfr2b–/– and Fgf10–/– mice exhibited a cleft palate, with disruption occurring in palatogenesis during the initial stages of development prior to shelf elevation, whilst Shh expression was downregulated [131]. Additionally in Fgfr2b–/– mice, cell proliferation decreased in both the palatal epithelium and mesenchyme. This elucidated a mechanism whereby mesenchymal Fgf10 regulates the epithelial expression of Sonic Hedgehog (Shh), a downstream target of Fgf10/Fgfr2b signaling, which then signals back to the mesenchyme. Further, it has more recently been revealed that a Shh-Foxf-Fgf18-Shh circuit contributes to the palate development molecular network whereby Foxf1 and Foxf2 repressing Fgf18 expression in the palatal mesenchyme in order to regulate epithelial palatal shelf growth in the downstream of Shh signaling [132].

Additional Information Regarding Abnormalities in FGFR Signalling

The abnormalities regarding the FGFR signalling pathways that have been discussed above are widely researched and reported on. However, there are many more conditions resulting from mutations in the FGFR signalling pathway and always ongoing research into these conditions in which it causes. For more information regarding the conditions mentioned above, and in general abnormalities of FGFR signalling, links to OMIM have been provided below.

About OMIM "Online Mendelian Inheritance in Man OMIM is a comprehensive, authoritative, and timely compendium of human genes and genetic phenotypes. The full-text, referenced overviews in OMIM contain information on all known mendelian disorders and over 12,000 genes. OMIM focuses on the relationship between phenotype and genotype. It is updated daily, and the entries contain copious links to other genetics resources." OMIM

Conditions Mentioned Above:


Fibroblast Growth Factor Receptor Subtypes:

FGF and FGFR Abnormalities in Cancer

Deregulation of FGF signaling pathways have been implicated in many types of human and animal cancers [1]. This deregulation can be heritable or acquired during development or postnatally.

These abnormalities in signalling may arise from mutations in genes for FGF ligands, receptors, or downstream signaling pathways, as well as modified protein or gene expression of ligands or receptors at the transcriptional level or via gene amplification. Mechanisms of FGF ligand activation include aberrant expression and gene amplification leading to ligand overexpression, resulting in excessive FGF signaling. Secondary mutations that increase diffusion of FGFs through tissue or increase affinity for FGFRs may also contribute. FGFRs can also be activated by mutations, gene amplification leading to receptor overexpression, or by translocations resulting in activating fusions with adjacent genes. Activation of FGFRs by somatic acquisition of missense mutations is another common tumorigenic mechanism. Each of these mechanisms ultimately results in cancer initiation or progression.

Recent advancements in understanding these pathogenic mechanisms in FGFs and FGFRs has led to therapeutic approaches for a variety of cancers. [133]

The following table describes the types of FGF and FGFR genetic mutations associated with numerous of the most common cancers in humans and their prevalence.


Carcinoma Type FGF/FGFRs Associated % Affected (if known)
Bladder
  • over expression of FGF2 [134]
  • amplification, translocation and missense mutation in FGFR3 [135] [136]
  • FGFR3 was amplified in 3% [137]
  • missense mutations in FGFR3 have been observed in 35% [138]
Breast
  • amplification of FGF3 and FGF4, over expression of FGF8 [139] [140] and FGF10 [141]
  • amplification of FGFR1 and FGFR2 [142], over expression and missense mutation in FGFR3 [143], missense mutation in FGFR4 [144]
  • FGFR1 amplification identified in 20% lobular breast cancer [142]
  • FGFR4 amplification found in 10% primary breast tumors [145]
Colorectal
  • amplification and missense mutation in FGFR2 and FGFR3 [146]
  • missense mutation in FGFR4 [147]
  • FGFR4 mutation present in 57% of patients [147]
Glioblastoma
  • over expression of FGF5 [148]
  • over expression and translocation of FGFR1, translocation of FGFR3 [149]
  • 3.1% exhibit FGFR1 or FGFR3 mutation
Hepatocellular
Leukemia & Lymphoma
  • translocation of FGFR1 [155]
Lung Adenocarcenoma
  • FGFR1 amplification identified in 3% [159]
Lung Squamous Cell
  • amplification of FGFR1 [160]
  • translocation of FGFR3 [161]
  • FGFR1 amplification identified in 21-28% cases [162] [163]
Lung Small Cell
  • over expression of FGF2 [164]
  • amplification of FGFR1 [165]
  • 43.7% exhibit FGFR1 amplification, with worse prognostic outcomes [165]
Lung Non-Small Cell
  • over expression FGF9 [166]
  • 10%, with 3-fold increase in likelihood of post-operative occurrence[166]
Melanoma [167]
  • over expression of FGF2
  • missense mutation and amplification of FGFR1
Ovarian
  • amplification of FGF1 [168], overexpression FGF16 [169]
  • amplification of FGFR1, over expression of FGFR4 [170] [171]
Pancreatic
  • amplification of FGFR1 [172]
Prostate
  • FGFR1 or FGFR2 was amplified in 47% of hormone resistant prostate cancers [181]

New and emerging research surrounding FGFRs

Promising Therapeutic Methods To Alleviate The Skeletal Phenotypes Resulting From Dysfunction FGFs/FGFRs

File:Bone signalling pathway1.gif
Signals regulating bone growth

A variety of studies have been conducted in order to investigate methods that will alleviate the skeletal phenotypes caused by dysfunctional FGFs/FGFRs signalling. In gain of function mutations, the major strategy of treatment is to reduce their excessive activities, subsequently alleviating the impaired cell functions, whilst in contrast, loss of function mutations or deficiency are treated by supplementation of related factors [182].

In order to prevent excessive intracellular signalling and to alleviate the symptoms of FGFs and FGFR-related genetic disorders, a variety of molecules targeting FGFRs or their tyrosine kinase were used. A soluble form of the Apert mutant, FGFR2, which lacked the transmembrane and cytoplasmic domains, will compete for ligand binding with FGFRs, thus enhancing the process of osteoblastic differentiation of cells in the osteosarcoma cell line transfected with the Apert mutant. Recently, it was found that FGFR2 may partially prevent craniosynostosis in the Apert mouse model [183]. There has also been an increase in the number of studies related to FGFR3-related skeleton disorders. A31, which is a tyrosine kinase inhibitor, is a capable of restoring normal expression of cell cycle regulators and allow pre-hypertonic chondrocytes to properly differentiate into hypertonic chondrocytes in cultured femurs from achondroplasia (ACH) mice[184]. In addition, further research has been able to develop a recombinant protein therapeutic approach which uses a soluble form of FGFR3, as a decoy receptor, in order to rescue the phenotype of ACH transgenic mice with no toxicity[185]. Another approach to target FGFR3 is to use an anti-FGFR3 antibody, however the antibody may carry a risk of an antibody-dependent cell cytotoxic reaction, which prevents its use in ACH.

Studies have also demonstrated that ERK, a molecule downstream of the FGFR signalling pathway, is responsible for retarded growth of long bones and premature fusion of the synchondroses caused by abnormal FGFR3 expression[186]. Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote the enlargement of the spinal canal and promote bone growth. From another study it was found that inhibition of ERK signalling may enlarge the narrowing of the spinal canal, thus alleviating neurological complications of ACH. [186]

FGFs and FGFRs in the development of hepatocellular carcinoma and possible treatments


Macroscopic image of hepatocellular carcinoma

Liver cancer, is the 5th most common type of cancer worldwide whereby approximately 90% of all liver cancers are hepatocellular carcinomas (HCC). Factors such as obesity and diabetes may serve as predisposing factors in the development of HCC, whereby cirrhosis is the overriding risk factor in the development of HCC. Cirrhosis is a chronic disease of the liver which is characterised by the degeneration of cells, inflammation and fibrous thickening of tissue[187].

With respect to this condition, FGF has been shown to play a major role in the progression and metastasis (spread) of HCC. Take for example, a study which revealed the presence of FGF2 expression being found only in the liver tissue of patients suffering from HCC, but not in those with normal and healthy liver tissue [188]. This study also revealed that raised serum FGF2 levels were largely associated with the progression of chronic liver disease too. Further investigations have also revealed that at least one member of the FGF8 subfamily was shown to be up-regulated in HCC patients. This subfamily was shown to enhance the survival of HCC cells, which is indicative of the notion that they play a vital role in enhancing the survival of HCC cells and thus are involved in the development and progression of HCC [189]. In addition to the actions of FGFs, FGFRs were shown to mediate the survival and proliferation of murine hepatoblasts and hepatic tumour initiating stem cells in part through activation of AKT-Beta-catenin-CBP pathway[190].

Recent research has now aimed to target FGF as a possible treatment to prevent the development and progression of HCC. Specific antibody targets against specific FGF families are being investigated such as anti-FGF19 monoclonal antibody which will selectively block the interaction of FGF19 with FGFR4, thus preventing the development of HCC as shown in mice[191]. An additional study revealed that anti-FGF19 antibody induced a reduction in the growth of colon tumours and also revealed the same result, in that HCC was prevented in mice treated with the antibody[192].

New and emerging research surrounding FGFRs

Promising Therapeutic Methods To Alleviate The Skeletal Phenotypes Resulting From Dysfunction FGFs/FGFRs

File:Bone signalling pathway1.gif
Signals regulating bone growth

A variety of studies have been conducted in order to investigate methods that will alleviate the skeletal phenotypes caused by dysfunctional FGFs/FGFRs signalling. In gain of function mutations, the major strategy of treatment is to reduce their excessive activities, subsequently alleviating the impaired cell functions, whilst in contrast, loss of function mutations or deficiency are treated by supplementation of related factors [193].

In order to prevent excessive intracellular signalling and to alleviate the symptoms of FGFs and FGFR-related genetic disorders, a variety of molecules targeting FGFRs or their tyrosine kinase were used. A soluble form of the Apert mutant, FGFR2, which lacked the transmembrane and cytoplasmic domains, will compete for ligand binding with FGFRs, thus enhancing the process of osteoblastic differentiation of cells in the osteosarcoma cell line transfected with the Apert mutant. Recently, it was found that FGFR2 may partially prevent craniosynostosis in the Apert mouse model [194]. There has also been an increase in the number of studies related to FGFR3-related skeleton disorders. A31, which is a tyrosine kinase inhibitor, is a capable of restoring normal expression of cell cycle regulators and allow pre-hypertonic chondrocytes to properly differentiate into hypertonic chondrocytes in cultured femurs from achondroplasia (ACH) mice[195]. In addition, further research has been able to develop a recombinant protein therapeutic approach which uses a soluble form of FGFR3, as a decoy receptor, in order to rescue the phenotype of ACH transgenic mice with no toxicity[196]. Another approach to target FGFR3 is to use an anti-FGFR3 antibody, however the antibody may carry a risk of an antibody-dependent cell cytotoxic reaction, which prevents its use in ACH.

Studies have also demonstrated that ERK, a molecule downstream of the FGFR signalling pathway, is responsible for retarded growth of long bones and premature fusion of the synchondroses caused by abnormal FGFR3 expression[186]. Genetic inactivation of ERK1 and ERK2 in chondrocytes can promote the enlargement of the spinal canal and promote bone growth. From another study it was found that inhibition of ERK signalling may enlarge the narrowing of the spinal canal, thus alleviating neurological complications of ACH. [186].

FGFs and FGFRs in the development of hepatocellular carcinoma and possible treatments


Macroscopic image of hepatocellular carcinoma

Liver cancer, is the 5th most common type of cancer worldwide whereby approximately 90% of all liver cancers are hepatocellular carcinomas (HCC). Factors such as obesity and diabetes may serve as predisposing factors in the development of HCC, whereby cirrhosis is the overriding risk factor in the development of HCC. Cirrhosis is a chronic disease of the liver which is characterised by the degeneration of cells, inflammation and fibrous thickening of tissue[197].

With respect to this condition, FGF has been shown to play a major role in the progression and metastasis (spread) of HCC. Take for example, a study which revealed the presence of FGF2 expression being found only in the liver tissue of patients suffering from HCC, but not in those with normal and healthy liver tissue [198]. This study also revealed that raised serum FGF2 levels were largely associated with the progression of chronic liver disease too. Further investigations have also revealed that at least one member of the FGF8 subfamily was shown to be up-regulated in HCC patients. This subfamily was shown to enhance the survival of HCC cells, which is indicative of the notion that they play a vital role in enhancing the survival of HCC cells and thus are involved in the development and progression of HCC [199]. In addition to the actions of FGFs, FGFRs were shown to mediate the survival and proliferation of murine hepatoblasts and hepatic tumour initiating stem cells in part through activation of AKT-Beta-catenin-CBP pathway[200].

Recent research has now aimed to target FGF as a possible treatment to prevent the development and progression of HCC. Specific antibody targets against specific FGF families are being investigated such as anti-FGF19 monoclonal antibody which will selectively block the interaction of FGF19 with FGFR4, thus preventing the development of HCC as shown in mice[201]. An additional study revealed that anti-FGF19 antibody induced a reduction in the growth of colon tumours and also revealed the same result, in that HCC was prevented in mice treated with the antibody[202].

Autoregulatory Loop Of Induction Between FGF10 And FGF8

FGFR2 is a membrane spanning receptor that acts as a receptor for members of the fibroblast growth factor family. By mutating the FGFR2 in mice, a number of novel findings were determined regarding the importance of this receptor [203]. None of the embryos with mutated FGFR2’s survived due to the resulting developmental deficits from a dysfunctional FGFR2. Furthermore, induction of FGF8 is blocked in the limb ectoderm and the expression of FGF10 in the underlying mesoderm is reduced. This highlights the importance of the FGFR2 receptor as well as indicating its involvement in a signalling loop between FGF8 and FGF10. Due to the functions of FGF8 and FGF10, it has been postulated that interaction between these two FGF members is imperative for limb bud formation, in the context of the epithelial – mesenchymal interaction.

Whilst the role of FGFR2 has been described in the context of FGF8 and FGF10, it is important to acknowledge that there are many other pathways that use these fibroblast growth factors and interrupting these will result in similarly disastrous issues. For example, by inhibiting B – catenin activity, limbs will become truncated, indicating FGF-10 being affected and FGF8 expression in the ectoderm was severely down regulated[204]. This shows how the signalling loop between FGF8 and FGF10 can be affected in many different ways and in this instance, by altering the amount of B – Catenin available to the embryo.

Further Information Regarding FGFR Signalling And Embryology

Recent Papers From PubMed
PubMed logo.gif

This table shows an automated computer PubMed search using the listed sub-heading term.

  • Therefore the list of references do not reflect any editorial selection of material based on content or relevance.
  • References appear in this list based upon the date of the actual page viewing.

References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.

Links: References | Discussion Page | Pubmed Most Recent | Journal Searches

Search term: FGF Signalling In Organogenesis

James D Glover, Kirsty L Wells, Franziska Matthäus, Kevin J Painter, William Ho, Jon Riddell, Jeanette A Johansson, Matthew J Ford, Colin A B Jahoda, Vaclav Klika, Richard L Mort, Denis J Headon Hierarchical patterning modes orchestrate hair follicle morphogenesis. PLoS Biol.: 2017, 15(7);e2002117 PubMed 28700594

Pengchun Yu, Kerstin Wilhelm, Alexandre Dubrac, Joe K Tung, Tiago C Alves, Jennifer S Fang, Yi Xie, Jie Zhu, Zehua Chen, Frederik De Smet, Jiasheng Zhang, Suk-Won Jin, Lele Sun, Hongye Sun, Richard G Kibbey, Karen K Hirschi, Nissim Hay, Peter Carmeliet, Thomas W Chittenden, Anne Eichmann, Michael Potente, Michael Simons FGF-dependent metabolic control of vascular development. Nature: 2017; PubMed 28467822

June Seok Heo, Hyun Ok Kim, Seung Yong Song, Dae Hyun Lew, Youjeong Choi, Sinyoung Kim Poly-L-lysine Prevents Senescence and Augments Growth in Culturing Mesenchymal Stem Cells Ex Vivo. Biomed Res Int: 2016, 2016;8196078 PubMed 27403437

Miguel Tillo, Camille Charoy, Quenten Schwarz, Charlotte H Maden, Kathryn Davidson, Alessandro Fantin, Christiana Ruhrberg 2- and 6-O-sulfated proteoglycans have distinct and complementary roles in cranial axon guidance and motor neuron migration. Development: 2016; PubMed 27048738

Liam J Rasch, Kyle J Martin, Rory L Cooper, Brian Metscher, Charlie Underwood, Gareth J Fraser An ancient dental gene set governs development and continuous regeneration of teeth in sharks. Dev. Biol.: 2016; PubMed 26845577

Glossary

Glossary definitions are sourced from lectures presented in the UNSW embryology course ANAT2341 (in addition to the glossary provided online in the course, which is linked to at the bottom of these selected terms which are related to this page.)

Term Definition
Animal Models Is a term used to describe animals studies that are used in research, they may have either an existing, inbred or induced disease/injury (that can be related to a human condition)
Apical Ectodermal Ridge (AER) Is a term used to describe the specialised thickening of the epithelium located towards the tip of the limb bud, it is formed by Wnt signalling and secrets FGFs which stimulates proliferation and outgrowth. It acts as a signalling centre ensuring appropriate limb development, including the patterning of the proximal-distal axis of the limb. For more information see Limb Development
Autosomal Dominant Inheritance A term used to describe the pattern of inheritance whereby one copy of a gene containing a mutation is sufficient to manifest into the disease. For more information see Genetic Inheritance
Craniosysnostosis Syndromes Are conditions where the cranial fibrous sutures prematurely fuse (ossify) resulting in a reduced space for the growing brain. The skull compensates for this fusion by growing parallel to the suture, meaning that the skull is abnormally shaped.
Ectoderm One of the initial germ cell layers formed during gastrulation (the others being endoderm and mesoderm). It is the outmost layer and is responsible for the formation of the nervous system and the entire epithelial layer of skin covering the embryo. For more information see Ectoderm
Endoderm One of the initial germ cell layers formed during gastrulation (the others being ectoderm and mesoderm). It is the innermost layer and is responsible for the formation epithelial lining of the gastrointestinal and respiratory tract, as well as contributions to the accessory organs of the GIT. For more information see Endoderm
Endochondral Ossification Is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being intramembranous ossification, see below.) This process involves an intermediate cartilage template and is essential for the formation and growth of long bones of the appendicular skeleton, face and spinal column. For more information see Bone Development
Fibroblast Growth Factors (FGFs) Are a family of 22 proteins, 18 of which are secreted signalling proteins (FGF1-10, and FGF16-23) and the other 4 are intracellular non-signalling proteins (iFGFs; FGF11-14)
Fibroblast Growth Factor Receptors (FGFRs) Are a family of 4 tyrosine kinase receptors (FGFR1-4) that interact with the signalling FGF proteins
Gastrulation Is the process whereby the trilaminar embryo formed containing the three germ layers (endoderm, ectoderm and mesoderm). For more information see Gastrulation
Germ Layers Refers to the three layers: (endoderm, ectoderm, mesoderm) which are primary cell layers from early in embryogenesis, which give rise to all tissues and organs
Hypospadias Is a term used to describe a male external genital abnormality resulting from a failure of the fusion of male urogenital folds, it is one of the most common penis abnormalities (1 in 300 births)
Intramembranous Ossification It is one of the two processes that are critical in the early stages of embryonic bone formation. (The other being endochondral ossification, see above.) It directly forms bone, it doesn’t require a cartilage template like endochondral ossification. It is responsible for the formation of bones of the skull and clavicles. For more information see Bone Development
Limb Bud The initial embryonic structures responsible for the formation of the paired upper and lower limbs. For more information see Limb Development
Lung Bud The initial embryonic structures responsible for the formation of the lungs. For more information see Respiratory Development
Mesenchymal Tissue (also Mesenchyme) is a term used to describe cellular organisation of undifferentiated embryonic connective tissue, Its contributions include both mesoderm and neural crest, which are responsible for forming most of the adult connective tissue
Mesoderm One of the initial germ cell layers formed during gastrulation (the others being ectoderm and endoderm). It is the middle layer and is responsible for the formation of all the connective tissue of the body (with the exception of the head region which has additional contributions from the neural crest.) For more information see Mesoderm
Missense Mutations A point mutation, replacement of a single nucleotide, which results in a different codon (coding for a different amino acid, this is considered to be a type of non-synonymous substitution)
Morphogenesis Is a term used to describe the process of development involving a change in form (shape)/size of either cells/tissues
Phenotype Is a term used to describe the observable characteristics of an organism and is related to the expressed genotype
RAS A family of related proteins which is expressed in all animal cell lineages and organs.
Sensory Placode Is a thickening of surface ectoderm present (paired) in the head region of the early embryo which contribute to a different component of each sensory system (including the otic placode, optic placode, olfactory placode.) For more information see Sensory Development
Skeletal Dysplasia A general term that relates to disorders affecting normal bone development

Below are links to a more extensive glossary if additional definitions are needed

A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Y | Z


Some external links were included throughout this page. External Links Notice - The dynamic nature of the internet may mean that some of these listed links may no longer function. If the link no longer works search the web with the link text or name. Links to any external commercial sites are provided for information purposes only and should never be considered an endorsement. UNSW Embryology is provided as an educational resource with no clinical information or commercial affiliation.

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 David M Ornitz, Nobuyuki Itoh The Fibroblast Growth Factor signaling pathway. Wiley Interdiscip Rev Dev Biol: 2014, 4(3);215-66 PubMed 25772309
  2. Quentin M Nunes, Yong Li, Changye Sun, Tarja K Kinnunen, David G Fernig Fibroblast growth factors as tissue repair and regeneration therapeutics. PeerJ: 2016, 4;e1535 PubMed 26793421
  3. Bernard Thisse, Christine Thisse Functions and regulations of fibroblast growth factor signaling during embryonic development. Dev. Biol.: 2005, 287(2);390-402 PubMed 16216232 [1]
  4. Cuiling Li, Xiaoling Xu, Danielle K Nelson, Trevor Williams, Michael R Kuehn, Chu-Xia Deng FGFR1 function at the earliest stages of mouse limb development plays an indispensable role in subsequent autopod morphogenesis. Development: 2005, 132(21);4755-64 PubMed 16207751
  5. Ulla Pirvola, Jukka Ylikoski, Ras Trokovic, Jean M Hébert, Susan K McConnell, Juha Partanen FGFR1 is required for the development of the auditory sensory epithelium. Neuron: 2002, 35(4);671-80 PubMed 12194867
  6. T P Yamaguchi, R A Conlon, J Rossant Expression of the fibroblast growth factor receptor FGFR-1/flg during gastrulation and segmentation in the mouse embryo. Dev. Biol.: 1992, 152(1);75-88 PubMed 1321062
  7. Jacob E Lazarus, Anita Hegde, Anenisia C Andrade, Ola Nilsson, Jeffrey Baron Fibroblast growth factor expression in the postnatal growth plate. Bone: 2007, 40(3);577-86 PubMed 17169623
  8. Anne L Jacob, Craig Smith, Juha Partanen, David M Ornitz Fibroblast growth factor receptor 1 signaling in the osteo-chondrogenic cell lineage regulates sequential steps of osteoblast maturation. Dev. Biol.: 2006, 296(2);315-28 PubMed 16815385
  9. Kathryn B Moore, Kathleen Mood, Ira O Daar, Sally A Moody Morphogenetic movements underlying eye field formation require interactions between the FGF and ephrinB1 signaling pathways. Dev. Cell: 2004, 6(1);55-67 PubMed 14723847
  10. A L Delezoide, C Benoist-Lasselin, L Legeai-Mallet, M Le Merrer, A Munnich, M Vekemans, J Bonaventure Spatio-temporal expression of FGFR 1, 2 and 3 genes during human embryo-fetal ossification. Mech. Dev.: 1998, 77(1);19-30 PubMed 9784595
  11. K G Peters, S Werner, G Chen, L T Williams Two FGF receptor genes are differentially expressed in epithelial and mesenchymal tissues during limb formation and organogenesis in the mouse. Development: 1992, 114(1);233-43 PubMed 1315677
  12. Brian U Ang, Ryan M Spivak, Hyun-Duck Nah, Richard E Kirschner Dura in the pathogenesis of syndromic craniosynostosis: fibroblast growth factor receptor 2 mutations in dural cells promote osteogenic proliferation and differentiation of osteoblasts. J Craniofac Surg: 2010, 21(2);462-7 PubMed 20489451
  13. Andrew O M Wilkie Bad bones, absent smell, selfish testes: the pleiotropic consequences of human FGF receptor mutations. Cytokine Growth Factor Rev.: 2005, 16(2);187-203 PubMed 15863034
  14. Machael L Cunningham, Marianne L Seto, Chootima Ratisoontorn, Carrie L Heike, Anne V Hing Syndromic craniosynostosis: from history to hydrogen bonds. Orthod Craniofac Res: 2007, 10(2);67-81 PubMed 17552943
  15. Akio Shimizu, Yuji Takashima, Misuzu Kurokawa-Seo FGFR3 isoforms have distinct functions in the regulation of growth and cell morphology. Biochem. Biophys. Res. Commun.: 2002, 290(1);113-20 PubMed 11779141
  16. K Peters, D Ornitz, S Werner, L Williams Unique expression pattern of the FGF receptor 3 gene during mouse organogenesis. Dev. Biol.: 1993, 155(2);423-30 PubMed 8432397
  17. J S Colvin, B A Bohne, G W Harding, D G McEwen, D M Ornitz Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nat. Genet.: 1996, 12(4);390-7 PubMed 8630492
  18. 18.0 18.1 David M Ornitz, Pierre J Marie FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev.: 2002, 16(12);1446-65 PubMed 12080084
  19. 19.0 19.1 A M Moon, A M Boulet, M R Capecchi Normal limb development in conditional mutants of Fgf4. Development: 2000, 127(5);989-96 PubMed 10662638
  20. Wen-Ya Zhou, Hong Zheng, Xiao-Ling Du, Ji-Long Yang Characterization of FGFR signaling pathway as therapeutic targets for sarcoma patients. Cancer Biol Med: 2016, 13(2);260-8 PubMed 27458533
  21. F Bellot, G Crumley, J M Kaplow, J Schlessinger, M Jaye, C A Dionne Ligand-induced transphosphorylation between different FGF receptors. EMBO J.: 1991, 10(10);2849-54 PubMed 1655404
  22. C J Powers, S W McLeskey, A Wellstein Fibroblast growth factors, their receptors and signaling. Endocr. Relat. Cancer: 2000, 7(3);165-97 PubMed 11021964
  23. M Mohammadi, A M Honegger, D Rotin, R Fischer, F Bellot, W Li, C A Dionne, M Jaye, M Rubinstein, J Schlessinger A tyrosine-phosphorylated carboxy-terminal peptide of the fibroblast growth factor receptor (Flg) is a binding site for the SH2 domain of phospholipase C-gamma 1. Mol. Cell. Biol.: 1991, 11(10);5068-78 PubMed 1656221
  24. Y R Hadari, H Kouhara, I Lax, J Schlessinger Binding of Shp2 tyrosine phosphatase to FRS2 is essential for fibroblast growth factor-induced PC12 cell differentiation. Mol. Cell. Biol.: 1998, 18(7);3966-73 PubMed 9632781
  25. Oxford University Press (2015, March 9) the FGF Signalling Pathway Retrieved from https://www.youtube.com/watch?v=DUBelRjjqvc
  26. W G Cox, A Hemmati-Brivanlou Caudalization of neural fate by tissue recombination and bFGF. Development: 1995, 121(12);4349-58 PubMed 8575335
  27. L Mathis, P M Kulesa, S E Fraser FGF receptor signalling is required to maintain neural progenitors during Hensen's node progression. Nat. Cell Biol.: 2001, 3(6);559-66 PubMed 11389440
  28. G R Martin The roles of FGFs in the early development of vertebrate limbs. Genes Dev.: 1998, 12(11);1571-86 PubMed 9620845 [2]
  29. Yasuhiko Kawakami, Concepción Rodríguez Esteban, Takaaki Matsui, Joaquín Rodríguez-León, Shigeaki Kato, Juan Carlos Izpisúa Belmonte Sp8 and Sp9, two closely related buttonhead-like transcription factors, regulate Fgf8 expression and limb outgrowth in vertebrate embryos. Development: 2004, 131(19);4763-74 PubMed 15358670 [3]
  30. M Lewandoski, X Sun, G R Martin Fgf8 signalling from the AER is essential for normal limb development. Nat. Genet.: 2000, 26(4);460-3 PubMed 11101846 [4]
  31. Xin Sun, Francesca V Mariani, Gail R Martin Functions of FGF signalling from the apical ectodermal ridge in limb development. Nature: 2002, 418(6897);501-8 PubMed 12152071 [5]
  32. Yo-Ichi Yamamoto-Shiraishi, Hiroaki Higuchi, Shigeki Yamamoto, Mie Hirano, Atsushi Kuroiwa Etv1 and Ewsr1 cooperatively regulate limb mesenchymal Fgf10 expression in response to apical ectodermal ridge-derived fibroblast growth factor signal. Dev. Biol.: 2014, 394(1);181-90 PubMed 25109552 [6]
  33. J F Fallon, A López, M A Ros, M P Savage, B B Olwin, B K Simandl FGF-2: apical ectodermal ridge growth signal for chick limb development. Science: 1994, 264(5155);104-7 PubMed 7908145 [7]
  34. E Laufer, C E Nelson, R L Johnson, B A Morgan, C Tabin Sonic hedgehog and Fgf-4 act through a signaling cascade and feedback loop to integrate growth and patterning of the developing limb bud. Cell: 1994, 79(6);993-1003 PubMed 8001146 [8]
  35. P H Crossley, S Martinez, G R Martin Midbrain development induced by FGF8 in the chick embryo. Nature: 1996, 380(6569);66-8 PubMed 8598907 [9]
  36. Itzel García (2012, July 9) Limb development [Video file]. Retrieved from https://www.youtube.com/watch?v=VpbdqGJ9LWk
  37. 37.0 37.1 37.2 37.3 David M Ornitz, Pierre J Marie Fibroblast growth factor signaling in skeletal development and disease. Genes Dev.: 2015, 29(14);1463-86 PubMed 26220993 [10]
  38. R Shiang, L M Thompson, Y Z Zhu, D M Church, T J Fielder, M Bocian, S T Winokur, J J Wasmuth Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell: 1994, 78(2);335-42 PubMed 7913883
  39. Caroline J Sheeba, Raquel P Andrade, Delphine Duprez, Isabel Palmeirim Comprehensive analysis of fibroblast growth factor receptor expression patterns during chick forelimb development. Int. J. Dev. Biol.: 2010, 54(10);1517-26 PubMed 21302260
  40. Joshua W Mugford, Petra Sipilä, Jill A McMahon, Andrew P McMahon Osr1 expression demarcates a multi-potent population of intermediate mesoderm that undergoes progressive restriction to an Osr1-dependent nephron progenitor compartment within the mammalian kidney. Dev. Biol.: 2008, 324(1);88-98 PubMed 18835385
  41. Y Miyazaki, K Oshima, A Fogo, B L Hogan, I Ichikawa Bone morphogenetic protein 4 regulates the budding site and elongation of the mouse ureter. J. Clin. Invest.: 2000, 105(7);863-73 PubMed 10749566
  42. 42.0 42.1 Richard Guillaume, Michel Bressan, Doris Herzlinger Paraxial mesoderm contributes stromal cells to the developing kidney. Dev. Biol.: 2009, 329(2);169-75 PubMed 19272374
  43. B Cancilla, M D Ford-Perriss, J F Bertram Expression and localization of fibroblast growth factors and fibroblast growth factor receptors in the developing rat kidney. Kidney Int.: 1999, 56(6);2025-39 PubMed 10594778
  44. V Fuhrmann, N Kinkl, T Leveillard, J Sahel, D Hicks Fibroblast growth factor receptor 4 (FGFR4) is expressed in adult rat and human retinal photoreceptors and neurons. J. Mol. Neurosci.: 2000, 13(1-2);187-97 PubMed 10691305
  45. A T Dudley, R E Godin, E J Robertson Interaction between FGF and BMP signaling pathways regulates development of metanephric mesenchyme. Genes Dev.: 1999, 13(12);1601-13 PubMed 10385628
  46. 46.0 46.1 K G Peters, S Werner, G Chen, L T Williams Two FGF receptor genes are differentially expressed in epithelial and mesenchymal tissues during limb formation and organogenesis in the mouse. Development: 1992, 114(1);233-43 PubMed 1315677
  47. Marissa L Gredler, Ashley W Seifert, Martin J Cohn Tissue-specific roles of Fgfr2 in development of the external genitalia. Development: 2015, 142(12);2203-12 PubMed 26081573
  48. R Murakami, T Mizuno Proximal-distal sequence of development of the skeletal tissues in the penis of rat and the inductive effect of epithelium. J Embryol Exp Morphol: 1986, 92;133-43 PubMed 3723059
  49. C Grothe, B Brand-Saberi, J Wilting, B Christ Fibroblast growth factor receptor 1 in skeletal and heart muscle cells: expression during early avian development and regulation after notochord transplantation. Dev. Dyn.: 1996, 206(3);310-7 PubMed 8896986
  50. Kentaro Suzuki, Yukiko Ogino, Ryutaro Murakami, Yoshihiko Satoh, Daniel Bachiller, Gen Yamada Embryonic development of mouse external genitalia: insights into a unique mode of organogenesis. Evol. Dev.: 2002, 4(2);133-41 PubMed 12004962
  51. T P Yamaguchi, A Bradley, A P McMahon, S Jones A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo. Development: 1999, 126(6);1211-23 PubMed 10021340
  52. R Haraguchi, K Suzuki, R Murakami, M Sakai, M Kamikawa, M Kengaku, K Sekine, H Kawano, S Kato, N Ueno, G Yamada Molecular analysis of external genitalia formation: the role of fibroblast growth factor (Fgf) genes during genital tubercle formation. Development: 2000, 127(11);2471-9 PubMed 10804187
  53. Marissa L Gredler, Ashley W Seifert, Martin J Cohn Tissue-specific roles of Fgfr2 in development of the external genitalia. Development: 2015, 142(12);2203-12 PubMed 26081573
  54. Doris K Wu, Matthew W Kelley Molecular mechanisms of inner ear development. Cold Spring Harb Perspect Biol: 2012, 4(8);a008409 PubMed 22855724
  55. Sarah Pauley, Tracy J Wright, Ulla Pirvola, David Ornitz, Kirk Beisel, Bernd Fritzsch Expression and function of FGF10 in mammalian inner ear development. Dev. Dyn.: 2003, 227(2);203-15 PubMed 12761848
  56. J S Colvin, B A Bohne, G W Harding, D G McEwen, D M Ornitz Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nat. Genet.: 1996, 12(4);390-7 PubMed 8630492
  57. J S Colvin, B Feldman, J H Nadeau, M Goldfarb, D M Ornitz Genomic organization and embryonic expression of the mouse fibroblast growth factor 9 gene. Dev. Dyn.: 1999, 216(1);72-88 PubMed 10474167
  58. U Pirvola, U Arumäe, M Moshnyakov, J Palgi, M Saarma, J Ylikoski Coordinated expression and function of neurotrophins and their receptors in the rat inner ear during target innervation. Hear. Res.: 1994, 75(1-2);131-44 PubMed 8071140
  59. S L Mansour, J M Goddard, M R Capecchi Mice homozygous for a targeted disruption of the proto-oncogene int-2 have developmental defects in the tail and inner ear. Development: 1993, 117(1);13-28 PubMed 8223243
  60. 60.0 60.1 60.2 60.3 Matthew J Anderson, Eileen Southon, Lino Tessarollo, Mark Lewandoski Fgf3-Fgf4-cis: A new mouse line for studying Fgf functions during mouse development. Genesis: 2015; PubMed 26666435
  61. Johan W Jonker, Jae Myoung Suh, Annette R Atkins, Maryam Ahmadian, Pingping Li, Jamie Whyte, Mingxiao He, Henry Juguilon, Yun-Qiang Yin, Colin T Phillips, Ruth T Yu, Jerrold M Olefsky, Robert R Henry, Michael Downes, Ronald M Evans A PPARγ-FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis. Nature: 2012, 485(7398);391-4 PubMed 22522926
  62. Yusuke Murata, Kyoji Nishio, Takayuki Mochiyama, Morichika Konishi, Masaya Shimada, Hiroya Ohta, Nobuyuki Itoh Fgf21 impairs adipocyte insulin sensitivity in mice fed a low-carbohydrate, high-fat ketogenic diet. PLoS ONE: 2013, 8(7);e69330 PubMed 23874946
  63. M Zhou, R L Sutliff, R J Paul, J N Lorenz, J B Hoying, C C Haudenschild, M Yin, J D Coffin, L Kong, E G Kranias, W Luo, G P Boivin, J J Duffy, S A Pawlowski, T Doetschman Fibroblast growth factor 2 control of vascular tone. Nat. Med.: 1998, 4(2);201-7 PubMed 9461194
  64. J E Schultz, S A Witt, M L Nieman, P J Reiser, S J Engle, M Zhou, S A Pawlowski, J N Lorenz, T R Kimball, T Doetschman Fibroblast growth factor-2 mediates pressure-induced hypertrophic response. J. Clin. Invest.: 1999, 104(6);709-19 PubMed 10491406
  65. 65.0 65.1 S Ortega, M Ittmann, S H Tsang, M Ehrlich, C Basilico Neuronal defects and delayed wound healing in mice lacking fibroblast growth factor 2. Proc. Natl. Acad. Sci. U.S.A.: 1998, 95(10);5672-7 PubMed 9576942
  66. A Montero, Y Okada, M Tomita, M Ito, H Tsurukami, T Nakamura, T Doetschman, J D Coffin, M M Hurley Disruption of the fibroblast growth factor-2 gene results in decreased bone mass and bone formation. J. Clin. Invest.: 2000, 105(8);1085-93 PubMed 10772653
  67. Collin Homer-Bouthiette, Thomas Doetschman, Liping Xiao, Marja M Hurley Knockout of Nuclear High Molecular Weight FGF2 Isoforms in Mice Modulates Bone and Phosphate Homeostasis. J. Biol. Chem.: 2014; PubMed 25389287
  68. S L Mansour, J M Goddard, M R Capecchi Mice homozygous for a targeted disruption of the proto-oncogene int-2 have developmental defects in the tail and inner ear. Development: 1993, 117(1);13-28 PubMed 8223243
  69. 69.0 69.1 Lisa D Urness, Steven B Bleyl, Tracy J Wright, Anne M Moon, Suzanne L Mansour Redundant and dosage sensitive requirements for Fgf3 and Fgf10 in cardiovascular development. Dev. Biol.: 2011, 356(2);383-97 PubMed 21664901
  70. 70.0 70.1 B Feldman, W Poueymirou, V E Papaioannou, T M DeChiara, M Goldfarb Requirement of FGF-4 for postimplantation mouse development. Science: 1995, 267(5195);246-9 PubMed 7809630
  71. 71.0 71.1 J Qiao, R Uzzo, T Obara-Ishihara, L Degenstein, E Fuchs, D Herzlinger FGF-7 modulates ureteric bud growth and nephron number in the developing kidney. Development: 1999, 126(3);547-54 PubMed 9876183
  72. Akiko Terauchi, Erin M Johnson-Venkatesh, Anna B Toth, Danish Javed, Michael A Sutton, Hisashi Umemori Distinct FGFs promote differentiation of excitatory and inhibitory synapses. Nature: 2010, 465(7299);783-7 PubMed 20505669
  73. X Sun, E N Meyers, M Lewandoski, G R Martin Targeted disruption of Fgf8 causes failure of cell migration in the gastrulating mouse embryo. Genes Dev.: 1999, 13(14);1834-46 PubMed 10421635
  74. Alan O Perantoni, Olga Timofeeva, Florence Naillat, Charmaine Richman, Sangeeta Pajni-Underwood, Catherine Wilson, Seppo Vainio, Lee F Dove, Mark Lewandoski Inactivation of FGF8 in early mesoderm reveals an essential role in kidney development. Development: 2005, 132(17);3859-71 PubMed 16049111
  75. M Lewandoski, X Sun, G R Martin Fgf8 signalling from the AER is essential for normal limb development. Nat. Genet.: 2000, 26(4);460-3 PubMed 11101846
  76. Raj K Ladher, Tracy J Wright, Anne M Moon, Suzanne L Mansour, Gary C Schoenwolf FGF8 initiates inner ear induction in chick and mouse. Genes Dev.: 2005, 19(5);603-13 PubMed 15741321
  77. J Xu, Z Liu, D M Ornitz Temporal and spatial gradients of Fgf8 and Fgf17 regulate proliferation and differentiation of midline cerebellar structures. Development: 2000, 127(9);1833-43 PubMed 10751172
  78. Christopher B Brown, Jennifer M Wenning, Min Min Lu, Douglas J Epstein, Erik N Meyers, Jonathan A Epstein Cre-mediated excision of Fgf8 in the Tbx1 expression domain reveals a critical role for Fgf8 in cardiovascular development in the mouse. Dev. Biol.: 2004, 267(1);190-202 PubMed 14975726
  79. X Sun, E N Meyers, M Lewandoski, G R Martin Targeted disruption of Fgf8 causes failure of cell migration in the gastrulating mouse embryo. Genes Dev.: 1999, 13(14);1834-46 PubMed 10421635
  80. Andrew C White, Jingsong Xu, Yongjun Yin, Craig Smith, Gregory Schmid, David M Ornitz FGF9 and SHH signaling coordinate lung growth and development through regulation of distinct mesenchymal domains. Development: 2006, 133(8);1507-17 PubMed 16540513
  81. J S Colvin, R P Green, J Schmahl, B Capel, D M Ornitz Male-to-female sex reversal in mice lacking fibroblast growth factor 9. Cell: 2001, 104(6);875-89 PubMed 11290325
  82. Irene H Hung, Kai Yu, Kory J Lavine, David M Ornitz FGF9 regulates early hypertrophic chondrocyte differentiation and skeletal vascularization in the developing stylopod. Dev. Biol.: 2007, 307(2);300-13 PubMed 17544391
  83. pubmed>18653563</pubmed>
  84. Denise Al Alam, Frederic G Sala, Sheryl Baptista, Rosanna Galzote, Soula Danopoulos, Caterina Tiozzo, Philip Gage, Tracy Grikscheit, David Warburton, Mark R Frey, Saverio Bellusci FGF9-Pitx2-FGF10 signaling controls cecal formation in mice. Dev. Biol.: 2012, 369(2);340-8 PubMed 22819677
  85. 85.0 85.1 85.2 85.3 Kory J Lavine, Kai Yu, Andrew C White, Xiuqin Zhang, Craig Smith, Juha Partanen, David M Ornitz Endocardial and epicardial derived FGF signals regulate myocardial proliferation and differentiation in vivo. Dev. Cell: 2005, 8(1);85-95 PubMed 15621532
  86. Yongshun Lin, Lijie Chen, Chunhong Lin, Yongde Luo, Robert Y L Tsai, Fen Wang Neuron-derived FGF9 is essential for scaffold formation of Bergmann radial fibers and migration of granule neurons in the cerebellum. Dev. Biol.: 2009, 329(1);44-54 PubMed 19232523
  87. J S Colvin, A C White, S J Pratt, D M Ornitz Lung hypoplasia and neonatal death in Fgf9-null mice identify this gene as an essential regulator of lung mesenchyme. Development: 2001, 128(11);2095-106 PubMed 11493531
  88. 88.0 88.1 88.2 88.3 88.4 H Min, D M Danilenko, S A Scully, B Bolon, B D Ring, J E Tarpley, M DeRose, W S Simonet Fgf-10 is required for both limb and lung development and exhibits striking functional similarity to Drosophila branchless. Genes Dev.: 1998, 12(20);3156-61 PubMed 9784490
  89. Yolanda Alvarez, Maria Teresa Alonso, Victor Vendrell, Laura Cecilia Zelarayan, Pablo Chamero, Thomas Theil, Michael R Bösl, Shigeaki Kato, Mark Maconochie, Dieter Riethmacher, Thomas Schimmang Requirements for FGF3 and FGF10 during inner ear formation. Development: 2003, 130(25);6329-38 PubMed 14623822
  90. Tracy J Wright, Suzanne L Mansour Fgf3 and Fgf10 are required for mouse otic placode induction. Development: 2003, 130(15);3379-90 PubMed 12810586
  91. Tina Jaskoll, George Abichaker, Daniel Witcher, Frederic G Sala, Saverio Bellusci, Mohammad K Hajihosseini, Michael Melnick FGF10/FGFR2b signaling plays essential roles during in vivo embryonic submandibular salivary gland morphogenesis. BMC Dev. Biol.: 2005, 5;11 PubMed 15972105
  92. Jacqueline M Veltmaat, Frédéric Relaix, Lendy T Le, Klaus Kratochwil, Frédéric G Sala, Wendy van Veelen, Ritva Rice, Bradley Spencer-Dene, Arnaud A Mailleux, David P Rice, Jean Paul Thiery, Saverio Bellusci Gli3-mediated somitic Fgf10 expression gradients are required for the induction and patterning of mammary epithelium along the embryonic axes. Development: 2006, 133(12);2325-35 PubMed 16720875
  93. Frédéric G Sala, Pierre-Marie Del Moral, Caterina Tiozzo, Denise Al Alam, David Warburton, Tracy Grikscheit, Jacqueline M Veltmaat, Saverio Bellusci FGF10 controls the patterning of the tracheal cartilage rings via Shh. Development: 2011, 138(2);273-82 PubMed 21148187
  94. Ritva Rice, Bradley Spencer-Dene, Elaine C Connor, Amel Gritli-Linde, Andrew P McMahon, Clive Dickson, Irma Thesleff, David P C Rice Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate. J. Clin. Invest.: 2004, 113(12);1692-700 PubMed 15199404
  95. Denise Al Alam, Frederic G Sala, Sheryl Baptista, Rosanna Galzote, Soula Danopoulos, Caterina Tiozzo, Philip Gage, Tracy Grikscheit, David Warburton, Mark R Frey, Saverio Bellusci FGF9-Pitx2-FGF10 signaling controls cecal formation in mice. Dev. Biol.: 2012, 369(2);340-8 PubMed 22819677
  96. Qing-Feng Wu, Liu Yang, Shuai Li, Qiong Wang, Xiao-Bin Yuan, Xiang Gao, Lan Bao, Xu Zhang Fibroblast growth factor 13 is a microtubule-stabilizing protein regulating neuronal polarization and migration. Cell: 2012, 149(7);1549-64 PubMed 22726441
  97. 97.0 97.1 David F Wozniak, Maolei Xiao, Lin Xu, Kelvin A Yamada, David M Ornitz Impaired spatial learning and defective theta burst induced LTP in mice lacking fibroblast growth factor 14. Neurobiol. Dis.: 2007, 26(1);14-26 PubMed 17236779
  98. Qing Wang, Mark E Bardgett, Michael Wong, David F Wozniak, Junyang Lou, Benjamin D McNeil, Chen Chen, Anthony Nardi, David C Reid, Kelvin Yamada, David M Ornitz Ataxia and paroxysmal dyskinesia in mice lacking axonally transported FGF14. Neuron: 2002, 35(1);25-38 PubMed 12123606
  99. Joshua W Vincentz, John R McWhirter, Cornelis Murre, Antonio Baldini, Yasuhide Furuta Fgf15 is required for proper morphogenesis of the mouse cardiac outflow tract. Genesis: 2005, 41(4);192-201 PubMed 15789410
  100. Ugo Borello, Inma Cobos, Jason E Long, John R McWhirter, Cornelis Murre, John L R Rubenstein FGF15 promotes neurogenesis and opposes FGF8 function during neocortical development. Neural Dev: 2008, 3;17 PubMed 18625063
  101. Takeshi Inagaki, Mihwa Choi, Antonio Moschetta, Li Peng, Carolyn L Cummins, Jeffrey G McDonald, Guizhen Luo, Stacey A Jones, Bryan Goodwin, James A Richardson, Robert D Gerard, Joyce J Repa, David J Mangelsdorf, Steven A Kliewer Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab.: 2005, 2(4);217-25 PubMed 16213224
  102. Joshua W Vincentz, John R McWhirter, Cornelis Murre, Antonio Baldini, Yasuhide Furuta Fgf15 is required for proper morphogenesis of the mouse cardiac outflow tract. Genesis: 2005, 41(4);192-201 PubMed 15789410
  103. J Xu, Z Liu, D M Ornitz Temporal and spatial gradients of Fgf8 and Fgf17 regulate proliferation and differentiation of midline cerebellar structures. Development: 2000, 127(9);1833-43 PubMed 10751172
  104. Jeremy A Cholfin, John L R Rubenstein Patterning of frontal cortex subdivisions by Fgf17. Proc. Natl. Acad. Sci. U.S.A.: 2007, 104(18);7652-7 PubMed 17442747
  105. 105.0 105.1 Hiroko Usui, Masaki Shibayama, Norihiko Ohbayashi, Morichika Konishi, Shinji Takada, Nobuyuki Itoh Fgf18 is required for embryonic lung alveolar development. Biochem. Biophys. Res. Commun.: 2004, 322(3);887-92 PubMed 15336546
  106. Jeffrey A Whitsett, Jean C Clark, Lara Picard, Jay W Tichelaar, Susan E Wert, Nobuyuki Itoh, Anne-Karina T Perl, Mildred T Stahlman Fibroblast growth factor 18 influences proximal programming during lung morphogenesis. J. Biol. Chem.: 2002, 277(25);22743-9 PubMed 11927601
  107. Laura Cinque, Alison Forrester, Rosa Bartolomeo, Maria Svelto, Rossella Venditti, Sandro Montefusco, Elena Polishchuk, Edoardo Nusco, Antonio Rossi, Diego L Medina, Roman Polishchuk, Maria Antonietta De Matteis, Carmine Settembre FGF signalling regulates bone growth through autophagy. Nature: 2015, 528(7581);272-5 PubMed 26595272
  108. Hila Barak, Sung-Ho Huh, Shuang Chen, Cécile Jeanpierre, Jelena Martinovic, Mélanie Parisot, Christine Bole-Feysot, Patrick Nitschké, Rémi Salomon, Corinne Antignac, David M Ornitz, Raphael Kopan FGF9 and FGF20 maintain the stemness of nephron progenitors in mice and man. Dev. Cell: 2012, 22(6);1191-207 PubMed 22698282
  109. Andrew C Lysaght, Quan Yuan, Yi Fan, Neil Kalwani, Paul Caruso, MaryBeth Cunnane, Beate Lanske, Konstantina M Stanković FGF23 deficiency leads to mixed hearing loss and middle ear malformation in mice. PLoS ONE: 2014, 9(9);e107681 PubMed 25243481
  110. 110.0 110.1 Takashi Shimada, Makoto Kakitani, Yuji Yamazaki, Hisashi Hasegawa, Yasuhiro Takeuchi, Toshiro Fujita, Seiji Fukumoto, Kazuma Tomizuka, Takeyoshi Yamashita Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J. Clin. Invest.: 2004, 113(4);561-8 PubMed 14966565
  111. R L Johnson, C J Tabin Molecular models for vertebrate limb development. Cell: 1997, 90(6);979-90 PubMed 9323126
  112. 112.0 112.1 J W Saunders, C Reuss Inductive and axial properties of prospective wing-bud mesoderm in the chick embryo. Dev. Biol.: 1974, 38(1);41-50 PubMed 4826292
  113. M J Cohn, J C Izpisúa-Belmonte, H Abud, J K Heath, C Tickle Fibroblast growth factors induce additional limb development from the flank of chick embryos. Cell: 1995, 80(5);739-46 PubMed 7889567
  114. A Vogel, C Rodriguez, J C Izpisúa-Belmonte Involvement of FGF-8 in initiation, outgrowth and patterning of the vertebrate limb. Development: 1996, 122(6);1737-50 PubMed 8674413
  115. Omar A Ibrahimi, Brian K Yeh, Anna V Eliseenkova, Fuming Zhang, Shaun K Olsen, Makoto Igarashi, Stuart A Aaronson, Robert J Linhardt, Moosa Mohammadi Analysis of mutations in fibroblast growth factor (FGF) and a pathogenic mutation in FGF receptor (FGFR) provides direct evidence for the symmetric two-end model for FGFR dimerization. Mol. Cell. Biol.: 2005, 25(2);671-84 PubMed 15632068
  116. R Shiang, L M Thompson, Y Z Zhu, D M Church, T J Fielder, M Bocian, S T Winokur, J J Wasmuth Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell: 1994, 78(2);335-42 PubMed 7913883
  117. David Aviezer, Myriam Golembo, Avner Yayon Fibroblast growth factor receptor-3 as a therapeutic target for Achondroplasia--genetic short limbed dwarfism. Curr Drug Targets: 2003, 4(5);353-65 PubMed 12816345
  118. J Bonaventure, F Rousseau, L Legeai-Mallet, M Le Merrer, A Munnich, P Maroteaux Common mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene account for achondroplasia, hypochondroplasia, and thanatophoric dwarfism. Am. J. Med. Genet.: 1996, 63(1);148-54 PubMed 8723101
  119. Heidi G Parker, Bridgett M VonHoldt, Pascale Quignon, Elliott H Margulies, Stephanie Shao, Dana S Mosher, Tyrone C Spady, Abdel Elkahloun, Michele Cargill, Paul G Jones, Cheryl L Maslen, Gregory M Acland, Nathan B Sutter, Keiichi Kuroki, Carlos D Bustamante, Robert K Wayne, Elaine A Ostrander An expressed fgf4 retrogene is associated with breed-defining chondrodysplasia in domestic dogs. Science: 2009, 325(5943);995-8 PubMed 19608863
  120. A O Wilkie Craniosynostosis: genes and mechanisms. Hum. Mol. Genet.: 1997, 6(10);1647-56 PubMed 9300656
  121. 121.0 121.1 121.2 121.3 Chad M Teven, Evan M Farina, Jane Rivas, Russell R Reid Fibroblast growth factor (FGF) signaling in development and skeletal diseases. Genes Dis: 2014, 1(2);199-213 PubMed 25679016
  122. M M Cohen Pfeiffer syndrome update, clinical subtypes, and guidelines for differential diagnosis. Am. J. Med. Genet.: 1993, 45(3);300-7 PubMed 8434615
  123. L R Cornejo-Roldan, E Roessler, M Muenke Analysis of the mutational spectrum of the FGFR2 gene in Pfeiffer syndrome. Hum. Genet.: 1999, 104(5);425-31 PubMed 10394936
  124. wyscrvr (2011, March 23) Pfeiffer Syndrome [Video file]. Retrieved from https://www.youtube.com/watch?v=UKYcDm2QHtU
  125. David M Ornitz, Pierre J Marie Fibroblast growth factor signaling in skeletal development and disease. Genes Dev.: 2015, 29(14);1463-86 PubMed 26220993
  126. O A Ibrahimi, A V Eliseenkova, A N Plotnikov, K Yu, D M Ornitz, M Mohammadi Structural basis for fibroblast growth factor receptor 2 activation in Apert syndrome. Proc. Natl. Acad. Sci. U.S.A.: 2001, 98(13);7182-7 PubMed 11390973
  127. Hong Wang, Tianxiao Zhang, Tao Wu, Jacqueline B Hetmanski, Ingo Ruczinski, Holger Schwender, Kung Yee Liang, Tanda Murray, M Daniele Fallin, Richard J Redett, Gerald V Raymond, Sheng-Chih Jin, Yah-Huei Wu Chou, Philip Kuo-Ting Chen, Vincent Yeow, Samuel S Chong, Felicia S H Cheah, Sun Ha Jee, Ethylin W Jabs, Alan F Scott, Terri H Beaty The FGF and FGFR Gene Family and Risk of Cleft Lip With or Without Cleft Palate. Cleft Palate Craniofac. J.: 2013, 50(1);96-103 PubMed 22074045
  128. Ritva Rice, Bradley Spencer-Dene, Elaine C Connor, Amel Gritli-Linde, Andrew P McMahon, Clive Dickson, Irma Thesleff, David P C Rice Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate. J. Clin. Invest.: 2004, 113(12);1692-700 PubMed 15199404
  129. Weijie Wu, Shuping Gu, Cheng Sun, Wei He, Xiaohua Xie, Xihai Li, Wenduo Ye, Chunlin Qin, Yiping Chen, Jing Xiao, Chao Liu Altered FGF Signaling Pathways Impair Cell Proliferation and Elevation of Palate Shelves. PLoS ONE: 2015, 10(9);e0136951 PubMed 26332583
  130. M W Ferguson Palate development. Development: 1988, 103 Suppl;41-60 PubMed 3074914
  131. Ritva Rice, Bradley Spencer-Dene, Elaine C Connor, Amel Gritli-Linde, Andrew P McMahon, Clive Dickson, Irma Thesleff, David P C Rice Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate. J. Clin. Invest.: 2004, 113(12);1692-700 PubMed 15199404
  132. Jingyue Xu, Han Liu, Yu Lan, Bruce J Aronow, Vladimir V Kalinichenko, Rulang Jiang A Shh-Foxf-Fgf18-Shh Molecular Circuit Regulating Palate Development. PLoS Genet.: 2016, 12(1);e1005769 PubMed 26745863
  133. Masaru Katoh, Hitoshi Nakagama FGF receptors: cancer biology and therapeutics. Med Res Rev: 2014, 34(2);280-300 PubMed 23696246
  134. Shahrokh F Shariat, Ramy F Youssef, Amit Gupta, Daher C Chade, Pierre I Karakiewicz, Hendrik Isbarn, Claudio Jeldres, Arthur I Sagalowsky, Raheela Ashfaq, Yair Lotan Association of angiogenesis related markers with bladder cancer outcomes and other molecular markers. J. Urol.: 2010, 183(5);1744-50 PubMed 20299037
  135. Silvia Hernández, Agustí Toll, Eulàlia Baselga, Adriana Ribé, Javier Azua-Romeo, Ramon M Pujol, Francisco X Real Fibroblast growth factor receptor 3 mutations in epidermal nevi and associated low grade bladder tumors. J. Invest. Dermatol.: 2007, 127(7);1664-6 PubMed 17255960
  136. Sarah V Williams, Carolyn D Hurst, Margaret A Knowles Oncogenic FGFR3 gene fusions in bladder cancer. Hum. Mol. Genet.: 2013, 22(4);795-803 PubMed 23175443
  137. Anna Fischbach, Anja Rogler, Ramona Erber, Robert Stoehr, Richard Poulsom, Axel Heidenreich, Birte-Swantje Schneevoigt, Sven Hauke, Arndt Hartmann, Ruth Knuechel, Jürgen Veeck, Nadine T Gaisa Fibroblast growth factor receptor (FGFR) gene amplifications are rare events in bladder cancer. Histopathology: 2015, 66(5);639-49 PubMed 24898159
  138. D Cappellen, C De Oliveira, D Ricol, S de Medina, J Bourdin, X Sastre-Garau, D Chopin, J P Thiery, F Radvanyi Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nat. Genet.: 1999, 23(1);18-20 PubMed 10471491
  139. C Zammit, R Coope, J J Gomm, S Shousha, C L Johnston, R C Coombes Fibroblast growth factor 8 is expressed at higher levels in lactating human breast and in breast cancer. Br. J. Cancer: 2002, 86(7);1097-103 PubMed 11953856
  140. S K Marsh, G S Bansal, C Zammit, R Barnard, R Coope, D Roberts-Clarke, J J Gomm, R C Coombes, C L Johnston Increased expression of fibroblast growth factor 8 in human breast cancer. Oncogene: 1999, 18(4);1053-60 PubMed 10023681
  141. Vassiliki Theodorou, Mandy Boer, Britta Weigelt, Jos Jonkers, Martin van der Valk, John Hilkens Fgf10 is an oncogene activated by MMTV insertional mutagenesis in mouse mammary tumors and overexpressed in a subset of human breast carcinomas. Oncogene: 2004, 23(36);6047-55 PubMed 15208658
  142. 142.0 142.1 Eleonora Brunello, Matteo Brunelli, Giuseppe Bogina, Anna Caliò, Erminia Manfrin, Alessia Nottegar, Marco Vergine, Annamaria Molino, Emilio Bria, Francesco Massari, Giampaolo Tortora, Sara Cingarlini, Serena Pedron, Marco Chilosi, Giuseppe Zamboni, Keith Miller, Guido Martignoni, Franco Bonetti FGFR-1 amplification in metastatic lymph-nodal and haematogenous lobular breast carcinoma. J. Exp. Clin. Cancer Res.: 2012, 31;103 PubMed 23270564
  143. C Zammit, R Barnard, J Gomm, R Coope, S Shousha, C Coombes, C Johnston Altered intracellular localization of fibroblast growth factor receptor 3 in human breast cancer. J. Pathol.: 2001, 194(1);27-34 PubMed 11329138
  144. Christoph Thussbas, Jorg Nahrig, Sylvia Streit, Johannes Bange, Monika Kriner, Ronald Kates, Kurt Ulm, Marion Kiechle, Heinz Hoefler, Axel Ullrich, Nadia Harbeck FGFR4 Arg388 allele is associated with resistance to adjuvant therapy in primary breast cancer. J. Clin. Oncol.: 2006, 24(23);3747-55 PubMed 16822847
  145. S Jaakkola, P Salmikangas, S Nylund, J Partanen, E Armstrong, S Pyrhönen, P Lehtovirta, H Nevanlinna Amplification of fgfr4 gene in human breast and gynecological cancers. Int. J. Cancer: 1993, 54(3);378-82 PubMed 8099571
  146. J H Jang, K H Shin, J G Park Mutations in fibroblast growth factor receptor 2 and fibroblast growth factor receptor 3 genes associated with human gastric and colorectal cancers. Cancer Res.: 2001, 61(9);3541-3 PubMed 11325814
  147. 147.0 147.1 Yanwei Ye, Yingqiang Shi, Ye Zhou, Chunyan Du, Chunmeng Wang, Heqin Zhan, Biqiang Zheng, Xi Cao, Meng-Hong Sun, Hong Fu The fibroblast growth factor receptor-4 Arg388 allele is associated with gastric cancer progression. Ann. Surg. Oncol.: 2010, 17(12);3354-61 PubMed 20844967
  148. S Allerstorfer, G Sonvilla, H Fischer, S Spiegl-Kreinecker, C Gauglhofer, U Setinek, T Czech, C Marosi, J Buchroithner, J Pichler, R Silye, T Mohr, K Holzmann, B Grasl-Kraupp, B Marian, M Grusch, J Fischer, M Micksche, W Berger FGF5 as an oncogenic factor in human glioblastoma multiforme: autocrine and paracrine activities. Oncogene: 2008, 27(30);4180-90 PubMed 18362893
  149. Devendra Singh, Joseph Minhow Chan, Pietro Zoppoli, Francesco Niola, Ryan Sullivan, Angelica Castano, Eric Minwei Liu, Jonathan Reichel, Paola Porrati, Serena Pellegatta, Kunlong Qiu, Zhibo Gao, Michele Ceccarelli, Riccardo Riccardi, Daniel J Brat, Abhijit Guha, Ken Aldape, John G Golfinos, David Zagzag, Tom Mikkelsen, Gaetano Finocchiaro, Anna Lasorella, Raul Rabadan, Antonio Iavarone Transforming fusions of FGFR and TACC genes in human glioblastoma. Science: 2012, 337(6099);1231-5 PubMed 22837387
  150. Shuji Uematsu, Toshihiro Higashi, Kazuhiro Nouso, Kazuya Kariyama, Shin-Ichiro Nakamura, Mayumi Suzuki, Harushige Nakatsukasa, Yoshiyuki Kobayashi, Tadashi Hanafusa, Takao Tsuji, Yasushi Shiratori Altered expression of vascular endothelial growth factor, fibroblast growth factor-2 and endostatin in patients with hepatocellular carcinoma. J. Gastroenterol. Hepatol.: 2005, 20(4);583-8 PubMed 15836707
  151. Christine Gauglhofer, Sandra Sagmeister, Waltraud Schrottmaier, Carina Fischer, Chantal Rodgarkia-Dara, Thomas Mohr, Stefan Stättner, Christoph Bichler, Daniela Kandioler, Fritz Wrba, Rolf Schulte-Hermann, Klaus Holzmann, Michael Grusch, Brigitte Marian, Walter Berger, Bettina Grasl-Kraupp Up-regulation of the fibroblast growth factor 8 subfamily in human hepatocellular carcinoma for cell survival and neoangiogenesis. Hepatology: 2011, 53(3);854-64 PubMed 21319186
  152. Seiki Miura, Noboru Mitsuhashi, Hiroaki Shimizu, Fumio Kimura, Hiroyuki Yoshidome, Masayuki Otsuka, Atsushi Kato, Takashi Shida, Daiki Okamura, Masaru Miyazaki Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma. BMC Cancer: 2012, 12;56 PubMed 22309595
  153. Christine Gauglhofer, Sandra Sagmeister, Waltraud Schrottmaier, Carina Fischer, Chantal Rodgarkia-Dara, Thomas Mohr, Stefan Stättner, Christoph Bichler, Daniela Kandioler, Fritz Wrba, Rolf Schulte-Hermann, Klaus Holzmann, Michael Grusch, Brigitte Marian, Walter Berger, Bettina Grasl-Kraupp Up-regulation of the fibroblast growth factor 8 subfamily in human hepatocellular carcinoma for cell survival and neoangiogenesis. Hepatology: 2011, 53(3);854-64 PubMed 21319186
  154. Christine Gauglhofer, Jakob Paur, Waltraud C Schrottmaier, Bettina Wingelhofer, Daniela Huber, Isabelle Naegelen, Christine Pirker, Thomas Mohr, Christine Heinzle, Klaus Holzmann, Brigitte Marian, Rolf Schulte-Hermann, Walter Berger, Georg Krupitza, Michael Grusch, Bettina Grasl-Kraupp Fibroblast growth factor receptor 4: a putative key driver for the aggressive phenotype of hepatocellular carcinoma. Carcinogenesis: 2014, 35(10);2331-8 PubMed 25031272
  155. S Xiao, S R Nalabolu, J C Aster, J Ma, L Abruzzo, E S Jaffe, R Stone, S M Weissman, T J Hudson, J A Fletcher FGFR1 is fused with a novel zinc-finger gene, ZNF198, in the t(8;13) leukaemia/lymphoma syndrome. Nat. Genet.: 1998, 18(1);84-7 PubMed 9425908
  156. Takatomo Yamayoshi, Takeshi Nagayasu, Keitarou Matsumoto, Takafumi Abo, Yoshitaka Hishikawa, Takehiko Koji Expression of keratinocyte growth factor/fibroblast growth factor-7 and its receptor in human lung cancer: correlation with tumour proliferative activity and patient prognosis. J. Pathol.: 2004, 204(1);110-8 PubMed 15307144
  157. Yongjun Yin, Tomoko Betsuyaku, Joel R Garbow, Jinbai Miao, Ramaswamy Govindan, David M Ornitz Rapid induction of lung adenocarcinoma by fibroblast growth factor 9 signaling through FGF receptor 3. Cancer Res.: 2013, 73(18);5730-41 PubMed 23867472
  158. Daisuke Arai, Ahmed E Hegab, Kenzo Soejima, Aoi Kuroda, Kota Ishioka, Hiroyuki Yasuda, Katsuhiko Naoki, Kagawa Shizuko, Junko Hamamoto, Yongjun Yin, David M Ornitz, Tomoko Betsuyaku Characterization of the cell of origin and propagation potential of the fibroblast growth factor 9-induced mouse model of lung adenocarcinoma. J. Pathol.: 2014; PubMed 25413587
  159. 159.0 159.1 Amit Dutt, Alex H Ramos, Peter S Hammerman, Craig Mermel, Jeonghee Cho, Tanaz Sharifnia, Ajit Chande, Kumiko Elisa Tanaka, Nicolas Stransky, Heidi Greulich, Nathanael S Gray, Matthew Meyerson Inhibitor-sensitive FGFR1 amplification in human non-small cell lung cancer. PLoS ONE: 2011, 6(6);e20351 PubMed 21666749
  160. Florian Malchers, Felix Dietlein, Jakob Schöttle, Xin Lu, Lucia Nogova, Kerstin Albus, Lynnette Fernandez-Cuesta, Johannes M Heuckmann, Oliver Gautschi, Joachim Diebold, Dennis Plenker, Masyar Gardizi, Matthias Scheffler, Marc Bos, Danila Seidel, Frauke Leenders, André Richters, Martin Peifer, Alexandra Florin, Prathama S Mainkar, Nagaraju Karre, Srivari Chandrasekhar, Julie George, Steffi Silling, Daniel Rauh, Thomas Zander, Roland T Ullrich, H Christian Reinhardt, Francois Ringeisen, Reinhard Büttner, Lukas C Heukamp, Jürgen Wolf, Roman K Thomas Cell-autonomous and non-cell-autonomous mechanisms of transformation by amplified FGFR1 in lung cancer. Cancer Discov: 2014, 4(2);246-57 PubMed 24302556
  161. Ian J Majewski, Lorenza Mittempergher, Nadia M Davidson, Astrid Bosma, Stefan M Willems, Hugo M Horlings, Iris de Rink, Liliana Greger, Gerrit K J Hooijer, Dennis Peters, Petra M Nederlof, Ingrid Hofland, Jeroen de Jong, Jelle Wesseling, Roelof J C Kluin, Wim Brugman, Ron Kerkhoven, Frank Nieboer, Paul Roepman, Annegien Broeks, Thomas R Muley, Jacek Jassem, Jacek Niklinski, Nico van Zandwijk, Alvis Brazma, Alicia Oshlack, Michel van den Heuvel, René Bernards Identification of recurrent FGFR3 fusion genes in lung cancer through kinome-centred RNA sequencing. J. Pathol.: 2013, 230(3);270-6 PubMed 23661334
  162. Jonathan Weiss, Martin L Sos, Danila Seidel, Martin Peifer, Thomas Zander, Johannes M Heuckmann, Roland T Ullrich, Roopika Menon, Sebastian Maier, Alex Soltermann, Holger Moch, Patrick Wagener, Florian Fischer, Stefanie Heynck, Mirjam Koker, Jakob Schöttle, Frauke Leenders, Franziska Gabler, Ines Dabow, Silvia Querings, Lukas C Heukamp, Hyatt Balke-Want, Sascha Ansén, Daniel Rauh, Ingelore Baessmann, Janine Altmüller, Zoe Wainer, Matthew Conron, Gavin Wright, Prudence Russell, Ben Solomon, Elisabeth Brambilla, Christian Brambilla, Philippe Lorimier, Steinar Sollberg, Odd Terje Brustugun, Walburga Engel-Riedel, Corinna Ludwig, Iver Petersen, Jörg Sänger, Joachim Clement, Harry Groen, Wim Timens, Hannie Sietsma, Erik Thunnissen, Egbert Smit, Daniëlle Heideman, Federico Cappuzzo, Claudia Ligorio, Stefania Damiani, Michael Hallek, Rameen Beroukhim, William Pao, Bert Klebl, Matthias Baumann, Reinhard Buettner, Karen Ernestus, Erich Stoelben, Jürgen Wolf, Peter Nürnberg, Sven Perner, Roman K Thomas Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Sci Transl Med: 2010, 2(62);62ra93 PubMed 21160078
  163. Florian Malchers, Felix Dietlein, Jakob Schöttle, Xin Lu, Lucia Nogova, Kerstin Albus, Lynnette Fernandez-Cuesta, Johannes M Heuckmann, Oliver Gautschi, Joachim Diebold, Dennis Plenker, Masyar Gardizi, Matthias Scheffler, Marc Bos, Danila Seidel, Frauke Leenders, André Richters, Martin Peifer, Alexandra Florin, Prathama S Mainkar, Nagaraju Karre, Srivari Chandrasekhar, Julie George, Steffi Silling, Daniel Rauh, Thomas Zander, Roland T Ullrich, H Christian Reinhardt, Francois Ringeisen, Reinhard Büttner, Lukas C Heukamp, Jürgen Wolf, Roman K Thomas Cell-autonomous and non-cell-autonomous mechanisms of transformation by amplified FGFR1 in lung cancer. Cancer Discov: 2014, 4(2);246-57 PubMed 24302556
  164. K Ueno, Y Inoue, T Kawaguchi, S Hosoe, M Kawahara Increased serum levels of basic fibroblast growth factor in lung cancer patients: relevance to response of therapy and prognosis. Lung Cancer: 2001, 31(2-3);213-9 PubMed 11165400
  165. 165.0 165.1 Fang Yang, Yina Gao, Jingshu Geng, Di Qu, Qiuyue Han, Jiping Qi, Gongyan Chen Elevated expression of SOX2 and FGFR1 in correlation with poor prognosis in patients with small cell lung cancer. Int J Clin Exp Pathol: 2013, 6(12);2846-54 PubMed 24294370
  166. 166.0 166.1 Keiko Ohgino, Kenzo Soejima, Hiroyuki Yasuda, Yuichiro Hayashi, Junko Hamamoto, Katsuhiko Naoki, Daisuke Arai, Kota Ishioka, Takashi Sato, Hideki Terai, Shinnosuke Ikemura, Satoshi Yoda, Tetsuo Tani, Aoi Kuroda, Tomoko Betsuyaku Expression of fibroblast growth factor 9 is associated with poor prognosis in patients with resected non-small cell lung cancer. Lung Cancer: 2014, 83(1);90-6 PubMed 24239165
  167. J A Reed, N S McNutt, A P Albino Differential expression of basic fibroblast growth factor (bFGF) in melanocytic lesions demonstrated by in situ hybridization. Implications for tumor progression. Am. J. Pathol.: 1994, 144(2);329-36 PubMed 8311116
  168. Michael J Birrer, Michael E Johnson, Ke Hao, Kwong-Kwok Wong, Dong-Choon Park, Aaron Bell, William R Welch, Ross S Berkowitz, Samuel C Mok Whole genome oligonucleotide-based array comparative genomic hybridization analysis identified fibroblast growth factor 1 as a prognostic marker for advanced-stage serous ovarian adenocarcinomas. J. Clin. Oncol.: 2007, 25(16);2281-7 PubMed 17538174
  169. Moitri Basu, Satinath Mukhopadhyay, Uttara Chatterjee, Sib Sankar Roy FGF16 promotes invasive behavior of SKOV-3 ovarian cancer cells through activation of mitogen-activated protein kinase (MAPK) signaling pathway. J. Biol. Chem.: 2014, 289(3);1415-28 PubMed 24253043
  170. Christoph Thussbas, Jorg Nahrig, Sylvia Streit, Johannes Bange, Monika Kriner, Ronald Kates, Kurt Ulm, Marion Kiechle, Heinz Hoefler, Axel Ullrich, Nadia Harbeck FGFR4 Arg388 allele is associated with resistance to adjuvant therapy in primary breast cancer. J. Clin. Oncol.: 2006, 24(23);3747-55 PubMed 16822847
  171. Tarrik M Zaid, Tsz-Lun Yeung, Melissa S Thompson, Cecilia S Leung, Tom Harding, Ngai-Na Co, Rosie S Schmandt, Suet-Ying Kwan, Cristian Rodriguez-Aguay, Gabriel Lopez-Berestein, Anil K Sood, Kwong-Kwok Wong, Michael J Birrer, Samuel C Mok Identification of FGFR4 as a potential therapeutic target for advanced-stage, high-grade serous ovarian cancer. Clin. Cancer Res.: 2013, 19(4);809-20 PubMed 23344261
  172. Marko Kornmann, Toshiyuki Ishiwata, Kei Matsuda, Martha E Lopez, Kimi Fukahi, Goro Asano, Hans G Beger, Murray Korc IIIc isoform of fibroblast growth factor receptor 1 is overexpressed in human pancreatic cancer and enhances tumorigenicity of hamster ductal cells. Gastroenterology: 2002, 123(1);301-13 PubMed 12105858
  173. Nils C Lehnen, Anne von Mässenhausen, Holger Kalthoff, Hui Zhou, Tim Glowka, Ute Schütte, Tobias Höller, Katarina Riesner, Diana Boehm, Sabine Merkelbach-Bruse, Jutta Kirfel, Sven Perner, Ines Gütgemann Fibroblast growth factor receptor 1 gene amplification in pancreatic ductal adenocarcinoma. Histopathology: 2013, 63(2);157-66 PubMed 23808822
  174. Rolando Cuevas, Nina Korzeniewski, Yanis Tolstov, Markus Hohenfellner, Stefan Duensing FGF-2 disrupts mitotic stability in prostate cancer through the intracellular trafficking protein CEP57. Cancer Res.: 2013, 73(4);1400-10 PubMed 23243019
  175. F Ropiquet, D Giri, B Kwabi-Addo, A Mansukhani, M Ittmann Increased expression of fibroblast growth factor 6 in human prostatic intraepithelial neoplasia and prostate cancer. Cancer Res.: 2000, 60(15);4245-50 PubMed 10945637
  176. V J Gnanapragasam, M C Robinson, C Marsh, C N Robson, F C Hamdy, H Y Leung FGF8 isoform b expression in human prostate cancer. Br. J. Cancer: 2003, 88(9);1432-8 PubMed 12778074
  177. Sanaz Memarzadeh, Li Xin, David J Mulholland, Alka Mansukhani, Hong Wu, Michael A Teitell, Owen N Witte Enhanced paracrine FGF10 expression promotes formation of multifocal prostate adenocarcinoma and an increase in epithelial androgen receptor. Cancer Cell: 2007, 12(6);572-85 PubMed 18068633
  178. Shu Feng, Olga Dakhova, Chad J Creighton, Michael Ittmann Endocrine fibroblast growth factor FGF19 promotes prostate cancer progression. Cancer Res.: 2013, 73(8);2551-62 PubMed 23440425
  179. Nathaniel Polnaszek, Bernard Kwabi-Addo, Jianghua Wang, Michael Ittmann FGF17 is an autocrine prostatic epithelial growth factor and is upregulated in benign prostatic hyperplasia. Prostate: 2004, 60(1);18-24 PubMed 15129425
  180. Hae Jong Kim, Kyeoung-Hwa Kim, Jaehyouk Lee, Jong Jin Oh, Hyun Sub Cheong, Ee Lin Wong, Beom-Seok Yang, Seok Soo Byun, Soon Chul Myung Single nucleotide polymorphisms in fibroblast growth factor 23 gene, FGF23, are associated with prostate cancer risk. BJU Int.: 2014, 114(2);303-10 PubMed 24053368
  181. 181.0 181.1 Joanne Edwards, N Sarath Krishna, Caroline J Witton, John M S Bartlett Gene amplifications associated with the development of hormone-resistant prostate cancer. Clin. Cancer Res.: 2003, 9(14);5271-81 PubMed 14614009
  182. Yukiho Tanimoto, Masahiko Yokozeki, Kenji Hiura, Kazuya Matsumoto, Hideki Nakanishi, Toshio Matsumoto, Pierre J Marie, Keiji Moriyama A soluble form of fibroblast growth factor receptor 2 (FGFR2) with S252W mutation acts as an efficient inhibitor for the enhanced osteoblastic differentiation caused by FGFR2 activation in Apert syndrome. J. Biol. Chem.: 2004, 279(44);45926-34 PubMed 15310757
  183. Vivek Shukla, Xavier Coumoul, Rui-Hong Wang, Hyun-Seok Kim, Chu-Xia Deng RNA interference and inhibition of MEK-ERK signaling prevent abnormal skeletal phenotypes in a mouse model of craniosynostosis. Nat. Genet.: 2007, 39(9);1145-50 PubMed 17694057
  184. Aurélie Jonquoy, Emilie Mugniery, Catherine Benoist-Lasselin, Nabil Kaci, Laurent Le Corre, Florent Barbault, Anne-Lise Girard, Yves Le Merrer, Patricia Busca, Laurent Schibler, Arnold Munnich, Laurence Legeai-Mallet A novel tyrosine kinase inhibitor restores chondrocyte differentiation and promotes bone growth in a gain-of-function Fgfr3 mouse model. Hum. Mol. Genet.: 2012, 21(4);841-51 PubMed 22072392
  185. Stéphanie Garcia, Béatrice Dirat, Thomas Tognacci, Nathalie Rochet, Xavier Mouska, Stéphanie Bonnafous, Stéphanie Patouraux, Albert Tran, Philippe Gual, Yannick Le Marchand-Brustel, Isabelle Gennero, Elvire Gouze Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice. Sci Transl Med: 2013, 5(203);203ra124 PubMed 24048522
  186. 186.0 186.1 186.2 186.3 W C Su, M Kitagawa, N Xue, B Xie, S Garofalo, J Cho, C Deng, W A Horton, X Y Fu Activation of Stat1 by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism. Nature: 1997, 386(6622);288-92 PubMed 9069288 Cite error: Invalid <ref> tag; name "PMID9069288" defined multiple times with different content
  187. Lindsey A Torre, Freddie Bray, Rebecca L Siegel, Jacques Ferlay, Joannie Lortet-Tieulent, Ahmedin Jemal Global cancer statistics, 2012. CA Cancer J Clin: 2015, 65(2);87-108 PubMed 25651787
  188. Hinako Tsunematsu, Tomohide Tatsumi, Keisuke Kohga, Masashi Yamamoto, Hiroshi Aketa, Takuya Miyagi, Atsushi Hosui, Naoki Hiramatsu, Tatsuya Kanto, Norio Hayashi, Tetsuo Takehara Fibroblast growth factor-2 enhances NK sensitivity of hepatocellular carcinoma cells. Int. J. Cancer: 2012, 130(2);356-64 PubMed 21351090
  189. Christine Gauglhofer, Sandra Sagmeister, Waltraud Schrottmaier, Carina Fischer, Chantal Rodgarkia-Dara, Thomas Mohr, Stefan Stättner, Christoph Bichler, Daniela Kandioler, Fritz Wrba, Rolf Schulte-Hermann, Klaus Holzmann, Michael Grusch, Brigitte Marian, Walter Berger, Bettina Grasl-Kraupp Up-regulation of the fibroblast growth factor 8 subfamily in human hepatocellular carcinoma for cell survival and neoangiogenesis. Hepatology: 2011, 53(3);854-64 PubMed 21319186
  190. Nirmala Mavila, David James, Sarah Utley, Nguyen Cu, Orly Coblens, Katrina Mak, C Bart Rountree, Michael Kahn, Kasper S Wang Fibroblast growth factor receptor-mediated activation of AKT-β-catenin-CBP pathway regulates survival and proliferation of murine hepatoblasts and hepatic tumor initiating stem cells. PLoS ONE: 2012, 7(11);e50401 PubMed 23308088
  191. L R Desnoyers, R Pai, R E Ferrando, K Hötzel, T Le, J Ross, R Carano, A D'Souza, J Qing, I Mohtashemi, A Ashkenazi, D M French Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models. Oncogene: 2008, 27(1);85-97 PubMed 17599042
  192. Rama Pai, Dorothy French, Ning Ma, Kathy Hotzel, Emile Plise, Laurent Salphati, Kenneth D R Setchell, Joseph Ware, Veronique Lauriault, Leah Schutt, Dylan Hartley, Donna Dambach Antibody-mediated inhibition of fibroblast growth factor 19 results in increased bile acids synthesis and ileal malabsorption of bile acids in cynomolgus monkeys. Toxicol. Sci.: 2012, 126(2);446-56 PubMed 22268002
  193. Yukiho Tanimoto, Masahiko Yokozeki, Kenji Hiura, Kazuya Matsumoto, Hideki Nakanishi, Toshio Matsumoto, Pierre J Marie, Keiji Moriyama A soluble form of fibroblast growth factor receptor 2 (FGFR2) with S252W mutation acts as an efficient inhibitor for the enhanced osteoblastic differentiation caused by FGFR2 activation in Apert syndrome. J. Biol. Chem.: 2004, 279(44);45926-34 PubMed 15310757
  194. Vivek Shukla, Xavier Coumoul, Rui-Hong Wang, Hyun-Seok Kim, Chu-Xia Deng RNA interference and inhibition of MEK-ERK signaling prevent abnormal skeletal phenotypes in a mouse model of craniosynostosis. Nat. Genet.: 2007, 39(9);1145-50 PubMed 17694057
  195. Aurélie Jonquoy, Emilie Mugniery, Catherine Benoist-Lasselin, Nabil Kaci, Laurent Le Corre, Florent Barbault, Anne-Lise Girard, Yves Le Merrer, Patricia Busca, Laurent Schibler, Arnold Munnich, Laurence Legeai-Mallet A novel tyrosine kinase inhibitor restores chondrocyte differentiation and promotes bone growth in a gain-of-function Fgfr3 mouse model. Hum. Mol. Genet.: 2012, 21(4);841-51 PubMed 22072392
  196. Stéphanie Garcia, Béatrice Dirat, Thomas Tognacci, Nathalie Rochet, Xavier Mouska, Stéphanie Bonnafous, Stéphanie Patouraux, Albert Tran, Philippe Gual, Yannick Le Marchand-Brustel, Isabelle Gennero, Elvire Gouze Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice. Sci Transl Med: 2013, 5(203);203ra124 PubMed 24048522
  197. Lindsey A Torre, Freddie Bray, Rebecca L Siegel, Jacques Ferlay, Joannie Lortet-Tieulent, Ahmedin Jemal Global cancer statistics, 2012. CA Cancer J Clin: 2015, 65(2);87-108 PubMed 25651787
  198. Hinako Tsunematsu, Tomohide Tatsumi, Keisuke Kohga, Masashi Yamamoto, Hiroshi Aketa, Takuya Miyagi, Atsushi Hosui, Naoki Hiramatsu, Tatsuya Kanto, Norio Hayashi, Tetsuo Takehara Fibroblast growth factor-2 enhances NK sensitivity of hepatocellular carcinoma cells. Int. J. Cancer: 2012, 130(2);356-64 PubMed 21351090
  199. Christine Gauglhofer, Sandra Sagmeister, Waltraud Schrottmaier, Carina Fischer, Chantal Rodgarkia-Dara, Thomas Mohr, Stefan Stättner, Christoph Bichler, Daniela Kandioler, Fritz Wrba, Rolf Schulte-Hermann, Klaus Holzmann, Michael Grusch, Brigitte Marian, Walter Berger, Bettina Grasl-Kraupp Up-regulation of the fibroblast growth factor 8 subfamily in human hepatocellular carcinoma for cell survival and neoangiogenesis. Hepatology: 2011, 53(3);854-64 PubMed 21319186
  200. Nirmala Mavila, David James, Sarah Utley, Nguyen Cu, Orly Coblens, Katrina Mak, C Bart Rountree, Michael Kahn, Kasper S Wang Fibroblast growth factor receptor-mediated activation of AKT-β-catenin-CBP pathway regulates survival and proliferation of murine hepatoblasts and hepatic tumor initiating stem cells. PLoS ONE: 2012, 7(11);e50401 PubMed 23308088
  201. L R Desnoyers, R Pai, R E Ferrando, K Hötzel, T Le, J Ross, R Carano, A D'Souza, J Qing, I Mohtashemi, A Ashkenazi, D M French Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models. Oncogene: 2008, 27(1);85-97 PubMed 17599042
  202. Rama Pai, Dorothy French, Ning Ma, Kathy Hotzel, Emile Plise, Laurent Salphati, Kenneth D R Setchell, Joseph Ware, Veronique Lauriault, Leah Schutt, Dylan Hartley, Donna Dambach Antibody-mediated inhibition of fibroblast growth factor 19 results in increased bile acids synthesis and ileal malabsorption of bile acids in cynomolgus monkeys. Toxicol. Sci.: 2012, 126(2);446-56 PubMed 22268002
  203. X Xu, M Weinstein, C Li, M Naski, R I Cohen, D M Ornitz, P Leder, C Deng Fibroblast growth factor receptor 2 (FGFR2)-mediated reciprocal regulation loop between FGF8 and FGF10 is essential for limb induction. Development: 1998, 125(4);753-65 PubMed 9435295
  204. Y Kawakami, J Capdevila, D Büscher, T Itoh, C Rodríguez Esteban, J C Izpisúa Belmonte WNT signals control FGF-dependent limb initiation and AER induction in the chick embryo. Cell: 2001, 104(6);891-900 PubMed 11290326