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Gail R Martin - One of the best experts on this subject based on the ideXlab platform.

  • increasing fgf4 expression in the mouse limb bud causes polysyndactyly and rescues the skeletal defects that result from loss of FGF8 function
    Development, 2006
    Co-Authors: George Minowada, Gail R Martin
    Abstract:

    A major function of the limb bud apical ectodermal ridge (AER) is to produce fibroblast growth factors (FGFs) that signal to the underlying mesenchyme. Previous studies have suggested that of the four FGF genes specifically expressed in the mouse AER, FGF8 is unique not only in its expression pattern, but also because it is the only such FGF gene that causes limb skeletal abnormalities when individually inactivated. However, when both FGF8 and Fgf4 are simultaneously inactivated in the AER, the limb does not develop. One possible explanation for these observations is that although both of these FGF family members contribute to limb development, FGF8 has functions that Fgf4 cannot perform. To test this hypothesis, we used a novel method to substitute Fgf4 for FGF8 expression in the developing limb bud by concomitantly activating a conditional Fgf4 gain-of-function allele and inactivating an FGF8 loss-of-function allele in the same cells via Cre-mediated recombination. Our data show that when Fgf4 is expressed in place of FGF8, all of the skeletal defects caused by inactivation of FGF8 are rescued, conclusively demonstrating that FGF4 can functionally replace FGF8 in limb skeletal development. We also show that the increase in FGF signaling that occurs when the Fgf4 gain-of-function allele is activated in a wild-type limb bud causes formation of a supernumerary posterior digit (postaxial polydactyly), as well as cutaneous syndactyly between all the digits. These data underscore the importance of controlling the level of FGF gene expression for normal limb development.

  • functions of fgf signalling from the apical ectodermal ridge in limb development
    Nature, 2002
    Co-Authors: Francesca V Mariani, Gail R Martin
    Abstract:

    To determine the role of fibroblast growth factor (FGF) signalling from the apical ectodermal ridge (AER), we inactivated Fgf4 and FGF8 in AER cells or their precursors at different stages of mouse limb development. We show that FGF4 and FGF8 regulate cell number in the nascent limb bud and are required for survival of cells located far from the AER. On the basis of the skeletal phenotypes observed, we conclude that these functions are essential to ensure that sufficient progenitor cells are available to form the normal complement of skeletal elements, and perhaps other limb tissues. In the complete absence of both FGF4 and FGF8 activities, limb development fails. We present a model to explain how the mutant phenotypes arise from FGF-mediated effects on limb bud size and cell survival.

  • functions of fgf signalling from the apical ectodermal ridge in limb development
    Nature, 2002
    Co-Authors: Francesca V Mariani, Gail R Martin
    Abstract:

    To determine the role of fibroblast growth factor (FGF) signalling from the apical ectodermal ridge (AER), we inactivated Fgf4 and FGF8 in AER cells or their precursors at different stages of mouse limb development. We show that FGF4 and FGF8 regulate cell number in the nascent limb bud and are required for survival of cells located far from the AER. On the basis of the skeletal phenotypes observed, we conclude that these functions are essential to ensure that sufficient progenitor cells are available to form the normal complement of skeletal elements, and perhaps other limb tissues. In the complete absence of both FGF4 and FGF8 activities, limb development fails. We present a model to explain how the mutant phenotypes arise from FGF-mediated effects on limb bud size and cell survival.

  • FGF8 signalling from the aer is essential for normal limb development
    Nature Genetics, 2000
    Co-Authors: Mark Lewandoski, Gail R Martin
    Abstract:

    Vertebrate limb development depends on signals from the apical ectodermal ridge (AER), which rims the distal tip of the limb bud1. Removal of the AER in chick results in limbs lacking distal skeletal elements2,3. Fibroblast growth factor (FGF) proteins can substitute for the AER (refs 4–7), suggesting that FGF signalling mediates AER activity. Of the four mouse Fgf genes (Fgf4 , FGF8, Fgf9, Fgf17) known to display AER-specific expression domains within the limb bud (AER-Fgfs), only FGF8 is expressed throughout the AER. Moreover, FGF8 expression precedes that of other AER-Fgfs (refs 8–13), suggesting that FGF8 may perform unique functions early in limb development6,7. In mice, loss of function of Fgf4 (refs 13,14), Fgf9 (D. Ornitz, pers. comm.) or Fgf17 (ref. 15) has no effect on limb formation. We report here that inactivating FGF8 in early limb ectoderm causes a substantial reduction in limb-bud size, a delay in Shh expression, misregulation of Fgf4 expression, and hypoplasia or aplasia of specific skeletal elements. Our data identify FGF8 as the only known AER-Fgf individually necessary for normal limb development, and provide insight into the function of Fgf signalling from the AER in the normal outgrowth and patterning of the limb.

  • conditional inactivation of fgf4 reveals complexity of signalling during limb bud development
    Nature Genetics, 2000
    Co-Authors: Xin Sun, Mark Lewandoski, Erik N Meyers, Yihsin Liu, Robert E Maxson, Gail R Martin
    Abstract:

    Development of the vertebrate limb bud depends on reciprocal interactions between the zone of polarizing activity (ZPA) and the apical ectodermal ridge (AER). Sonic hedgehog (SHH) and fibroblast growth factors (FGFs) are key signalling molecules produced in the ZPA and AER, respectively. Experiments in chicks suggested that SHH expression in the ZPA is maintained by FGF4 expression in the AER, and vice versa, providing a molecular mechanism for coordinating the activities of these two signalling centres. This SHH/FGF4 feedback loop model is supported by genetic evidence showing that Fgf4 expression is not maintained in Shh-/- mouse limbs. We report here that Shh expression is maintained and limb formation is normal when Fgf4 is inactivated in mouse limbs, thus contradicting the model. We also found that maintenance of Fgf9 and Fgf17 expression is dependent on Shh, whereas FGF8 expression is not. We discuss a model in which no individual Fgf expressed in the AER (AER-Fgf) is solely necessary to maintain Shh expression, but, instead, the combined activities of two or more AER-Fgfs function in a positive feedback loop with Shh to control limb development.

Nobuyuki Itoh - One of the best experts on this subject based on the ideXlab platform.

  • roles of fgfs as paracrine or endocrine signals in liver development health and disease
    Frontiers in Cell and Developmental Biology, 2016
    Co-Authors: Nobuyuki Itoh, Yoshiaki Nakayama, Morichika Konishi
    Abstract:

    The liver plays important roles in multiple processes including metabolism, the immune system, and detoxification and also has a unique capacity for regeneration. FGFs are growth factors that have diverse functions in development, health, and disease. The FGF family now comprises 22 members. Several FGFs have been shown to play roles as paracrine signals in liver development, health, and disease. FGF8 and FGF10 are involved in embryonic liver development, FGF7 and FGF9 in repair in response to liver injury, and FGF5, FGF8, FGF9, FGF17, and FGF18 in the development and progression of hepatocellular carcinoma. In contrast, FGF15/19 and FGF21 are endocrine signals. FGF15/19, which is produced in the ileum, is a negative regulator of bile acid metabolism and a stimulator of gallbladder filling. FGF15/19 is a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis. It is also required for hepatocellular carcinoma and liver regeneration. FGF21 is a hepatokine produced in the liver. FGF21 regulates glucose and lipid metabolism in white adipose tissue. Serum FGF21 levels are elevated in non-alcoholic fatty liver. FGF21 also protects against non-alcoholic fatty liver. These findings provide new insights into the roles of FGFs in the liver and potential therapeutic strategies for hepatic disorders.

  • fgf22 regulated by fgf3 FGF8 signaling is required for zebrafish midbrain development
    Biology Open, 2013
    Co-Authors: Ayumi Miyake, Nobuyuki Itoh
    Abstract:

    Fibroblast growth factor (Fgf) signaling plays important roles in various developmental processes including brain development. Here, we identified zebrafish fgf22 predominantly expressed in the posterior midbrain and anterior midbrain–hindbrain boundary (MHB) primordia during early embryonic brain development. To examine roles of Fgf22 in midbrain development, we analyzed fgf22 knockdown embryos. The fgf22 morphants were defective in proper formation of the MHB constriction and the midbrain. The knockdown of fgf22 caused decreased cell proliferation in the midbrain, expanded expression of roof plate and tegmental marker genes, and decreased expression of tectal marker genes, indicating that Fgf22 is required for cell proliferation, roof plate formation, and tectum specification in the midbrain. Fgf receptor 2b (Fgfr2b), a potential receptor for Fgf22, was also required, indicating that Fgf22 signaling is mediated through Fgfr2b. The floor plate and the MHB are crucial for the dorsoventral patterning of the midbrain through Hedgehog (Hh) and Fgf signaling, respectively. The fgf3/FGF8 double morphant phenotype was essentially similar to that of fgf22 morphants, whereas the phenotype caused by inhibition of Hh signaling was not. fgf3 and FGF8 were expressed earlier than fgf22 in the MHB primordium and Fgf3/FGF8 signaling was required for fgf22 expression in the posterior midbrain. Furthermore, fgf22 partially rescued the fgf3/FGF8 double morphant phenotype. The present results indicate Fgf22 to be involved in midbrain development downstream of Fgf3 and FGF8 in the MHB but not of Hh in the floor plate.

  • Fgf22 regulated by Fgf3/FGF8 signaling is required for zebrafish midbrain development.
    Biology Open, 2013
    Co-Authors: Ayumi Miyake, Nobuyuki Itoh
    Abstract:

    Fibroblast growth factor (Fgf) signaling plays important roles in various developmental processes including brain development. Here, we identified zebrafish fgf22 predominantly expressed in the posterior midbrain and anterior midbrain–hindbrain boundary (MHB) primordia during early embryonic brain development. To examine roles of Fgf22 in midbrain development, we analyzed fgf22 knockdown embryos. The fgf22 morphants were defective in proper formation of the MHB constriction and the midbrain. The knockdown of fgf22 caused decreased cell proliferation in the midbrain, expanded expression of roof plate and tegmental marker genes, and decreased expression of tectal marker genes, indicating that Fgf22 is required for cell proliferation, roof plate formation, and tectum specification in the midbrain. Fgf receptor 2b (Fgfr2b), a potential receptor for Fgf22, was also required, indicating that Fgf22 signaling is mediated through Fgfr2b. The floor plate and the MHB are crucial for the dorsoventral patterning of the midbrain through Hedgehog (Hh) and Fgf signaling, respectively. The fgf3/FGF8 double morphant phenotype was essentially similar to that of fgf22 morphants, whereas the phenotype caused by inhibition of Hh signaling was not. fgf3 and FGF8 were expressed earlier than fgf22 in the MHB primordium and Fgf3/FGF8 signaling was required for fgf22 expression in the posterior midbrain. Furthermore, fgf22 partially rescued the fgf3/FGF8 double morphant phenotype. The present results indicate Fgf22 to be involved in midbrain development downstream of Fgf3 and FGF8 in the MHB but not of Hh in the floor plate.

  • functional evolutionary history of the mouse fgf gene family
    Developmental Dynamics, 2008
    Co-Authors: Nobuyuki Itoh, David M Ornitz
    Abstract:

    Fibroblast Growth Factors (FGFs) are polypeptides with diverse activities in development and physiology. The mammalian Fgf family can be divided into the intracellular Fgf11/12/13/14 subfamily (iFGFs), the hormone-like Fgf15/21/23 subfamily (hFGFs), and the canonical Fgf subfamilies, including Fgf1/2/5, Fgf3/4/6, Fgf7/10/22, FGF8/17/18, and Fgf9/16/20. However, all Fgfs are evolutionarily related. We propose that an Fgf13-like gene is the ancestor of the iFgf subfamily and the most likely evolutionary ancestor of the entire Fgf family. Potential ancestors of the canonical and hFgf subfamilies, Fgf4-, Fgf5-, FGF8-, Fgf9-, Fgf10-, and Fgf15-like, appear to have derived from an Fgf13-like ancestral gene. Canonical FGFs function in a paracrine manner, while hFGFs function in an endocrine manner. We conclude that the ancestral Fgfs for these subfamilies acquired this functional diversity before the evolution of vertebrates. During the evolution of early vertebrates, the Fgf subfamilies further expanded to contain three or four members in each subfamily.

  • involvement of fibroblast growth factor fgf 18 FGF8 signaling in specification of left right asymmetry and brain and limb development of the chick embryo
    Mechanisms of Development, 2000
    Co-Authors: Hideyo Ohuchi, Sachie Kimura, Miki Watamoto, Nobuyuki Itoh
    Abstract:

    To elucidate roles of fibroblast growth factors (FGF)18 during vertebrate development, we examined expression patterns of Fgf18 in chick embryos and observed effects of FGF18 protein on the Hensen's node, isthmus, and limb buds. Fgf18 is expressed on the right side of the node before the expression of FGF8 starts. FGF18 protein can induce expression of FGF8 on the left side of the node, indicating involvement of both FGFs in specification of left-right asymmetry. In the developing brain, Fgf18 is expressed in the isthmus, following the FGF8 expression. Since Fgf18 is induced ectopically during formation of the second midbrain by FGF8 protein, both FGFs also elaborate midbrain development. In the limb bud, Fgf18 is expressed in the mesenchyme and ectopic application of FGF18 protein inhibits bone growth in the limb. FGF18 is thus likely an endogenous ligand of FGF receptor 3, whose mutation causes bone dysplasia in humans. These results demonstrate that the FGF18-FGF8 signaling is involved in various organizing activities and the signaling hierarchies between FGF18 and FGF8 seem to change during patterning of different structures.

Michael Ittmann - One of the best experts on this subject based on the ideXlab platform.

  • the role of fibroblast growth factors and their receptors in prostate cancer
    Endocrine-related Cancer, 2004
    Co-Authors: Bernard Kwabiaddo, Mustafa Ozen, Michael Ittmann
    Abstract:

    Prostate cancer is the most common malignancy in men in the USA and the second leading cause of cancer deaths. Fibroblast growth factors (FGFs), including FGF1 (acidic FGF), FGF2 (basic FGF), FGF6 and FGF8 are all expressed at increased levels in prostate cancer as paracrine and/or autocrine growth factors for the prostate cancer cells. In addition, increased mobilization of FGFs from the extracellular matrix in cancer tissues can increase the availability of FGFs to cancer cells. Prostate cancer epithelial cells express all four types of FGF receptors (FGFR-1 to -4) at variable frequencies. Expression of FGFR-1 and FGFR-4 is most closely linked to prostate cancer progression, while the role of FGFR-2 remains controversial. Activation of FGF receptors can activate multiple signal transduction pathways including the phospholipase Cgamma, phosphatidyl inositol 3-kinase, mitogen-activated protein kinase and signal transducers and activators of transcription (STAT) pathways, all of which play a role in prostate cancer progression. Sprouty proteins can negatively regulate FGF signal transduction, potentially limiting the impact of FGF signaling in prostate cancer, but in a significant fraction of prostate cancers there is decreased expression of Sprouty1 mRNA and protein. The effects of increased FGF receptor signaling are wide ranging and involve both the cancer cells and surrounding stroma, including the vasculature. The net result of increased FGF signaling includes enhanced proliferation, resistance to cell death, increased motility and invasiveness, increased angiogenesis, enhanced metastasis, resistance to chemotherapy and radiation and androgen independence, all of which can enhance tumor progression and clinical aggressiveness. For this reason, the FGF signaling system it is an attractive therapeutic target, particularly since therapies targeting FGF receptors and/or FGF signaling can affect both the tumor cells directly and tumor angiogenesis. A number of approaches that could target FGF receptors and/or FGF receptor signaling in prostate cancer are currently being developed.

  • fgf9 is an autocrine and paracrine prostatic growth factor expressed by prostatic stromal cells
    Journal of Cellular Physiology, 1999
    Co-Authors: Dipak Giri, Frederic Ropiquet, Michael Ittmann
    Abstract:

    Polypeptide growth factors, including members of the fibroblast growth factor (FGF) family, play an important role in the growth and maintenance of the normal prostate. We have found that FGF9 is expressed at high levels in the normal peripheral and transition zone of the human prostate. Analysis of FGF9 production by primary cultures of prostatic epithelial and stromal cells has shown that FGF9 is produced and secreted by the prostatic stromal cells. Neither of these processes appears to be modulated by androgens. Production of FGF9 by stromal cells in vivo was confirmed by immunohistochemistry. FGF9 is a potent mitogen for both prostatic epithelial and stromal cells in culture and is a more potent mitogen for these cells than either FGF2 or FGF7, two other FGFs expressed in the human prostate. FGF9 is an abundant secreted growth factor that can act as both a paracrine mitogen for epithelial cells and an autocrine mitogen for stromal cells. Western blot analysis of tissue extracts from the normal and hyperplastic transition zone shows that FGF9 is present at two to threefold higher levels in the hyperplastic transition zone. Overexpression of this paracrine and autocrine growth factor may play an important role in the epithelial and stromal proliferation in benign prostatic hyperplasia. J. Cell. Physiol. 180:53–60, 1999. © 1999 Wiley-Liss, Inc.

  • alterations in expression of basic fibroblast growth factor fgf 2 and its receptor fgfr 1 in human prostate cancer
    Clinical Cancer Research, 1999
    Co-Authors: Dipak Giri, Frederic Ropiquet, Michael Ittmann
    Abstract:

    Fibroblast growth factors (FGFs) play an important role in the growth and maintenance of the normal prostate. There is increasing evidence from both animal models and analysis of human prostate cancer cell lines that alterations of FGFs and/or FGF receptors (FGFRs) may play an important role in prostate cancer progression. To better define the role of FGF2 and FGF7 in human prostate cancer in vivo, we have quantified these two growth factors in clinically localized human prostate cancers and uninvolved prostate by ELISA and Western blotting and determined their localization by immunohistochemistry. The expression of two of the primary receptors for these growth factors, FGFR-1 and FGFR-2, were also analyzed by immunohistochemistry and Western blotting in these same samples. We have found that FGF2 is significantly increased in prostate cancers when compared with uninvolved prostate and that the FGF2 is present in the stromal fibroblasts and endothelial cells but not the cancer cells. In addition, we have observed overexpression of both FGFR-1 and FGFR-2 in the prostate cancer epithelial cells in a subset of prostate cancers and that such overexpression is correlated with poor differentiation. Thus, there is both an increase in FGF2 concentration in prostate cancers and an increased expression of a receptor capable of responding to this growth factor, establishing a potential paracrine stimulation of prostate cancer cells by the surrounding stromal cells, which may play an important role in prostate cancer progression.

Mark Lewandoski - One of the best experts on this subject based on the ideXlab platform.

  • a combined series of fgf9 and fgf18 mutant alleles identifies unique and redundant roles in skeletal development
    Developmental Biology, 2016
    Co-Authors: Irene H Hung, Mark Lewandoski, Gary C Schoenwolf, David M Ornitz
    Abstract:

    Fibroblast growth factor (FGF) signaling is a critical regulator of skeletal development. Fgf9 and Fgf18 are the only FGF ligands with identified functions in embryonic bone growth. Mice lacking Fgf9 or Fgf18 have distinct skeletal phenotypes; however, the extent of overlapping or redundant functions for these ligands and the stage-specific contributions of FGF signaling to chondrogenesis and osteogenesis are not known. To identify separate versus shared roles for FGF9 and FGF18, we generated a combined series of Fgf9 and Fgf18 null alleles. Analysis of embryos lacking alleles of Fgf9 and Fgf18 shows that both encoded ligands function redundantly to control all stages of skeletogenesis; however, they have variable potencies along the proximodistal limb axis, suggesting gradients of activity during formation of the appendicular skeleton. Congenital absence of both Fgf9 and Fgf18 results in a striking osteochondrodysplasia and revealed functions for FGF signaling in early proximal limb chondrogenesis. Additional defects were also noted in craniofacial bones, vertebrae, and ribs. Loss of alleles of Fgf9 and Fgf18 also affect the expression of genes encoding other key intrinsic skeletal regulators, including IHH, PTHLH (PTHrP), and RUNX2, revealing potential direct, indirect, and compensatory mechanisms to coordinate chondrogenesis and osteogenesis.

  • fgf3 fgf4 cis a new mouse line for studying fgf functions during mouse development
    Genesis, 2016
    Co-Authors: Matthew J Anderson, Eileen Southon, Lino Tessarollo, Mark Lewandoski
    Abstract:

    The fibroblast growth factor (FGF) family consists of 22 ligands in mice and humans. FGF signaling is vital for embryogenesis and, when dysregulated, can cause disease. Loss-of-function genetic analysis in the mouse has been crucial for understanding FGF function. Such analysis has revealed that multiple Fgfs sometimes function redundantly. Exploring such redundancy between Fgf3 and Fgf4 is currently impossible because both genes are located on chromosome 7, about 18.5 kb apart, making the frequency of interallelic cross-over between existing mutant alleles too infrequent to be practicable. Therefore, we retargeted Fgf3 and Fgf4 in cis, generating an Fgf3 null allele and a conditional Fgf4 allele, subject to Cre inactivation. To increase the frequency of cis targeting, we used an F1 embryonic stem cell line that contained 129/SvJae (129) and C57BL/6J (B6) chromosomes and targeting constructs isogenic to the 129 chromosome. We confirmed cis targeting by assaying for B6/129 allele-specific single-nucleotide polymorphisms. We demonstrated the utility of the Fgf3(Δ)-Fgf4(flox)-cis mouse line by showing that the caudal axis extension defects found in the Fgf3 mutants worsen when Fgf4 is also inactivated. This Fgf3(Δ)-Fgf4(flox)-cis line will be useful to study redundancy of these genes in a variety of tissues and stages in development.

  • bmp signals control limb bud interdigital programmed cell death by regulating fgf signaling
    Development, 2007
    Co-Authors: Sangeeta Pajniunderwood, Catherine P Wilson, Cindy Elder, Mark Lewandoski
    Abstract:

    In vertebrate limbs that lack webbing, the embryonic interdigit region is removed by programmed cell death (PCD). Established models suggest that bone morphogenetic proteins (BMPs) directly trigger such PCD, although no direct genetic evidence exists for this. Alternatively, BMPs might indirectly affect PCD by regulating fibroblast growth factors (FGFs), which act as cell survival factors. Here, we inactivated the mouse BMP receptor gene Bmpr1a specifically in the limb bud apical ectodermal ridge (AER), a source of FGF activity. Early inactivation completely prevents AER formation. However, inactivation after limb bud initiation causes an upregulation of two AER-FGFs, Fgf4 and FGF8, and a loss of interdigital PCD leading to webbed limbs. To determine whether excess FGF signaling inhibits interdigit PCD in these Bmpr1a mutant limbs, we performed double and triple AER-specific inactivations of Bmpr1a, Fgf4 and FGF8. Webbing persists in AER-specific inactivations of Bmpr1a and FGF8 owing to elevated Fgf4 expression. Inactivation of Bmpr1a, FGF8 and one copy of Fgf4 eliminates webbing. We conclude that during normal embryogenesis, BMP signaling to the AER indirectly regulates interdigit PCD by regulating AER-FGFs, which act as survival factors for the interdigit mesenchyme.

  • FGF8 signalling from the aer is essential for normal limb development
    Nature Genetics, 2000
    Co-Authors: Mark Lewandoski, Gail R Martin
    Abstract:

    Vertebrate limb development depends on signals from the apical ectodermal ridge (AER), which rims the distal tip of the limb bud1. Removal of the AER in chick results in limbs lacking distal skeletal elements2,3. Fibroblast growth factor (FGF) proteins can substitute for the AER (refs 4–7), suggesting that FGF signalling mediates AER activity. Of the four mouse Fgf genes (Fgf4 , FGF8, Fgf9, Fgf17) known to display AER-specific expression domains within the limb bud (AER-Fgfs), only FGF8 is expressed throughout the AER. Moreover, FGF8 expression precedes that of other AER-Fgfs (refs 8–13), suggesting that FGF8 may perform unique functions early in limb development6,7. In mice, loss of function of Fgf4 (refs 13,14), Fgf9 (D. Ornitz, pers. comm.) or Fgf17 (ref. 15) has no effect on limb formation. We report here that inactivating FGF8 in early limb ectoderm causes a substantial reduction in limb-bud size, a delay in Shh expression, misregulation of Fgf4 expression, and hypoplasia or aplasia of specific skeletal elements. Our data identify FGF8 as the only known AER-Fgf individually necessary for normal limb development, and provide insight into the function of Fgf signalling from the AER in the normal outgrowth and patterning of the limb.

  • conditional inactivation of fgf4 reveals complexity of signalling during limb bud development
    Nature Genetics, 2000
    Co-Authors: Xin Sun, Mark Lewandoski, Erik N Meyers, Yihsin Liu, Robert E Maxson, Gail R Martin
    Abstract:

    Development of the vertebrate limb bud depends on reciprocal interactions between the zone of polarizing activity (ZPA) and the apical ectodermal ridge (AER). Sonic hedgehog (SHH) and fibroblast growth factors (FGFs) are key signalling molecules produced in the ZPA and AER, respectively. Experiments in chicks suggested that SHH expression in the ZPA is maintained by FGF4 expression in the AER, and vice versa, providing a molecular mechanism for coordinating the activities of these two signalling centres. This SHH/FGF4 feedback loop model is supported by genetic evidence showing that Fgf4 expression is not maintained in Shh-/- mouse limbs. We report here that Shh expression is maintained and limb formation is normal when Fgf4 is inactivated in mouse limbs, thus contradicting the model. We also found that maintenance of Fgf9 and Fgf17 expression is dependent on Shh, whereas FGF8 expression is not. We discuss a model in which no individual Fgf expressed in the AER (AER-Fgf) is solely necessary to maintain Shh expression, but, instead, the combined activities of two or more AER-Fgfs function in a positive feedback loop with Shh to control limb development.

James A Thomson - One of the best experts on this subject based on the ideXlab platform.