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PubMed1994

Heparin-induced oligomerization of FGF molecules is responsible for FGF receptor dimerization, activation, and cell proliferation.

Heparin is required for fibroblast growth factor (FGF) stimulation of biological responses. Using isothermal titration calorimetry, we show that acidic FGF (aFGF) forms a 1:1 complex with the soluble extracellular domain of FGF receptor (FGFR). Heparin exerts its effect by binding to many molecules of aFGF. The resulting aFGF-heparin complex can bind to several receptor molecules, leading to FGFR dimerization. In two cell lines lacking endogenous heparan sulfate, exogenous heparin is required for FGFR dimerization, tyrosine kinase activation, c-fos mRNA transcription, and cell proliferation. Moreover, a synthetic heparin analog that binds monovalently to aFGF blocks FGFR dimerization, activation, and signaling via FGFR. We propose that heparin causes oligomerization of aFGF such that its binding to FGFR results in dimerization and activation. This represents a novel mechanism for transmembrane signaling and may account for the action of many heparin-bound growth factors.

Animals↗
PubMed1997

Differential control of murine aldose reductase and fibroblast growth factor (FGF)-regulated-1 gene expression in NIH 3T3 cells by FGF-1 treatment and hyperosmotic stress.

Aldose reductase (AR) is an NADPH-dependent aldo-keto reductase implicated in cellular osmoregulation and detoxification. Two distinct murine genes have been identified that are predicted to encode proteins with significant amino acid sequence identity with mouse AR: mouse vas deferens protein and fibroblast growth factor (FGF)-regulated-1 protein (FR-1). Here we report that the AR and FR-1 genes are differentially regulated in NIH 3T3 fibroblasts. FGF-1 stimulation of quiescent cells induces both AR and FR-1 mRNA levels, but the effect on FR-1 mRNA expression is significantly greater. FGF-1 treatment also increases FR-1 protein expression, as determined by Western-blot analysis using FR-1-specific polyclonal antiserum. Calf serum stimulation of quiescent cells increases AR mRNA expression but not FR-1 mRNA expression. Finally, when NIH 3T3 cells are grown in hypertonic medium, AR mRNA levels are significantly increased whereas FR-1 mRNA levels are only slightly up-regulated. These results indicate that the AR and FR-1 genes are differentially regulated in murine fibroblasts by two different growth-promoting agents and by hyperosmotic stress. Therefore these structurally related enzymes may have at least some distinct cellular functions; for example, although both AR and FR-1 activity may be important for the metabolic changes associated with cellular proliferation, AR may be the primary aldo-keto reductase involved in cellular osmoregulation.

3T3 Cells↗
PubMed2004

Targets of fibroblast growth factor 1 (FGF-1) and FGF-2 signaling involved in the invasive and tumorigenic behavior of carcinoma cells.

Fibroblast growth factor (FGF)-1 and -2 have potent biological activities implicated in malignant tumor development. Their autocrine and nonautocrine activity in tumor progression of carcinoma was investigated in the NBT-II cell system. Cells were manipulated to either produce and be autocrine for FGF-1 or -2 or to only produce but not respond to these factors. The autocrine cells are highly invasive and tumorigenic and the determination of specific targets of FGF/fibroblast growth factor receptor (FGFR) signaling was assessed. In vitro studies showed that nonautocrine cells behave like epithelial parental cells, whereas autocrine cells have a mesenchymal phenotype correlated with the overexpression of urokinase plasminogen activator receptor (uPAR), the internalization of E-cadherin, and the redistribution of beta-catenin from the cell surface to the cytoplasm and nucleus. uPAR was defined as an early target, whereas E-cadherin and the leukocyte common antigen-related protein-tyrosine phosphatase (LAR-PTP) were later targets of FGF signaling, with FGFR1 activation more efficient than FGFR2 at modulating these targets. Behavior of autocrine cells was consistent with a decrease of tumor-suppressive activities of both E-cadherin and LAR-PTP. These molecular analyses show that the potential of these two growth factors in tumor progression is highly dependent on specific FGFR signaling and highlights its importance as a target for antitumor therapy.

Animals↗
PubMed1993

Heparan sulfate proteoglycan and FGF receptor target basic FGF to different intracellular destinations.

Basic FGF is a prototype of a family of heparin binding growth factors that regulate a variety of cellular responses including cell growth, morphogenesis and differentiation. At least two families of receptors bind bFGF and could mediate its response: (1) tyrosine kinase-containing FGF receptors, designated FGFR-1 to FGFR-4, and (2) heparan sulfate proteoglycans that bind bFGF through their heparan sulfate chains. Both are known to undergo internalization and thus bFGF bound to the different receptors may be internalized via more than one pathway. It is not known whether the intracellular fate of bFGF differs depending upon which receptor binds it at the cell surface. To investigate the respective roles of these receptors in the intracellular targeting of bFGF, we utilized NMuMG cells that bind and internalize bFGF through their heparan sulfate proteoglycans, but do not express detectable levels of FGFRs nor respond to bFGF. Basic FGF conjugated to saporin (bFGF-saporin) was used as a probe to study targeting of bFGF by the different receptors. Saporin is a cytotoxin that has no effect on cells if added exogenously. However, it kills cells if it gains access to the cytoplasm. The NMuMG cells internalize bFGF-saporin but are not killed. Transfecting these cells with FGFR-1 results in bFGF-responsive cells, which bind and internalize bFGF through FGFR-1, and are killed. Removing the heparan sulfate from these cells eliminates killing by bFGF-saporin.(ABSTRACT TRUNCATED AT 250 WORDS)

3T3 Cells↗
PubMed1999

FGF-2 facilitates binding of SH3 domain of PLC-gamma1 to vinculin and SH2 domains to FGF receptor in corneal endothelial cells.

PURPOSE: To determine the cellular localization of the Src homology (SH)2 and SH3 domains of PLC-gamma1 and their cytoplasmic binding partners, living corneal endothelial cells were microinjected with the fusion proteins containing SH domains. METHODS: Fusion proteins were prepared from plasmid vectors, and the fusion proteins containing SH2-SH2 [(SH2)2], SH2-SH2-SH3 [(SH2)2-SH3] or SH3 were isolated using affinity chromatography. Following microinjection, immunolocalization was analyzed using confocal laser microscope. RESULTS: Microinjected SH domains were targeted to the subcellular location following stimulation with FGF-2: the SH3 domain appeared to be targeted to cytoskeleton; the (SH2)2 domain showed a dual localization in cytoplasm and plasma membrane; the (SH2)2-SH3 domain was predominantly localized at membrane and perinuclear sites. In the absence of stimulation by FGF-2, the microinjected fusion proteins remained at the injection sites. When cytoplasmic binding partners were determined by double-staining, the SH3 domain demonstrated colocalization with vinculin: the staining profile of the SH3 domain was identical to that of vinculin, which demonstrates characteristic punctated profiles. The punctated staining of SH3 disappears toward the basal membrane, while that of vinculin remains in all confocal optical sections. On the other hand, some fraction of the (SH2)2 domain was colocalized with FGF receptor at the membrane site. When PLC-gamma1 and F-actin were double-stained, the endogenous PLC-gamma1 demonstrated a diffuse cytoplasmic staining and/or perinuclear staining, while phalloidin staining demonstrated that all cells have filamentous cytoplasmic distribution of F-actin. CONCLUSIONS: These findings indicate that the SH3 domain directs PLC-gamma1 to bind to vinculin and that the SH2 domains may mediate the binding of PLC-gamma1 to receptor tyrosine kinase. Furthermore, they suggest that phosphorylation is not required for targeting of PLC-gamma1 to membrane or cytoskeleton sites.

Actins↗
PubMed2005

Isolation of Xenopus FGF-8b and comparison with FGF-8a.

The Xenopus FGF-8a and FGF-8b isoforms have been reported to be neural crest and neuronal inducers, respectively. However, cloning of Xenopus FGF-8b (XFGF-8b) has not been reported previously and the two isoforms do not seem to have been clearly distinguished in Xenopus experiments. Here, we describe the cloning and expression of XFGF-8b and compare the effects of the two isoforms. XFGF-8b has an 11 amino acid insert in its N-terminal region compared with XFGF-8a. Both isoforms are expressed in the anterior neural regions of the early embryo, and in the apical ectodermal ridge of limb buds and tips of growing digits in the larval stages. However, XFGF-8b is more abundant than XFGF-8a throughout early development. The two isoforms are also regulated in similar fashion by retinoic acid in early development. However, although both XFGF-8a and XFGF-8b induce ectopic neurogenesis, only XFGF-8a appears to be involved in neural crest induction.

Amino Acid Sequence↗
PubMed1993

[Heterocomplex formation between high and low affinity FGF receptors is mediated by the formation of a FGF dimer].

Interactions between the two classes of fibroblast growth factor receptors 1) the high affinity receptors (HAR) a membrane glycoprotein containing an intrinsic tyrosine kinase activity, 2) low affinity receptors (LAR) cell surface proteoglycans containing heparan sulfate side chains (HSPG), and aFGF (MW: 15.5 kDa) were studied in bovine lens epithelial (BEL) cells. By Scatchard analysis of the aFGF binding to the BEL cell surface, we show that heparin at 10 micrograms/ml abolishes completely aFGF binding to LAR and reduces by half the number of aFGF HAR. By using cross-linking experiments, aFGF-HAR complexes are present in two forms (150 kDa and 135 kDa). Addition of heparin at 10 micrograms/ml abolishes the formation of the 150 kDa complex and does not affect the 135 kDa complex. Furthermore, binding of aFGF to LAR induces the spontaneous formation of a 31 kDa aFGF dimer. The dimerization process of aFGF on LAR is abolished by addition of heparin. During aFGF internalization at 37 degrees C, we have shown that aFGF-dimer is internalized, accumulated and degraded in the cell as is the 15.5 kDa native form. Heparin at 10 micrograms/ml suppresses specifically aFGF dimer internalization and reduces by half the total amount of internalized aFGF native form. Moreover, after aFGF binding and internalization, the affinity of HAR for aFGF increases concomitantly with its downregulation. Heparin does not seem to affect this phenomenon. All these results strongly suggest that an heteroreceptor dimer-aFGF complex (150 kDa) is formed by one molecule of HAR associated to one molecule of LAR through their respective interaction with a very stable homodimer of aFGF. Such a three component receptor complex induced by FGF dimerization may be a general process of FGF receptor activation which could explain the diversity of the biological response to FGF of different cell type expressing different HAR and LAR or HSPG.

Animals↗
PubMed1995

Cloned multipotential precursors from the mouse cerebrum require FGF-2, whereas glial restricted precursors are stimulated with either FGF-2 or EGF.

Fibroblast growth factor-2 (FGF-2) and epidermal growth factor (EGF) have both been reported to stimulate precursors in the developing CNS. To clarify these effects, we used clonal analysis to determine the lineage potential of precursors stimulated with each factor, at two stages of development. It was found that in cells isolated from the cerebrum of embryonic day 17 (E17) mice, FGF-2 stimulated both a multipotential precursor, which gave rise to neurons and astrocytes, and a committed glial precursor. In contrast, EGF only stimulated the glial restricted precursor. Thus, it appears that the multipotential cell, previously identified to be present at E10, remains selectively responsive to FGF-2, and that the EGF responsiveness observed at E17 reflects the presence of a new restricted class of precursors, rather than a switch in factor specificity of the multipotential cell.

Animals↗
PubMed1993

Spatio-temporal distribution of acidic and basic FGF indicates a role for FGF in rat lens morphogenesis.

As part of an investigation into the role of FGF in lens development, we have studied the distribution of both aFGF and bFGF during eye morphogenesis from embryonic days 10 to 18 (E10-E18) in the rat. For aFGF, reactivity was found only in ectoderm at E10, prior to contact between the optic vesicle and presumptive lens ectoderm. During lens placode formation (E11) there was a transient, diffuse reactivity for aFGF in anterior optic vesicle cells directly apposed to the labelled ectoderm of the lens placode. At E12 the diffuse reactivity of the lens placode had changed to a discrete localisation along the basolateral surfaces of differentiating cells in the lens pit. Similar reactivity was associated with neuroblasts along the inner margin of the optic cup. At the early lens vesicle stage (E13) the baso-lateral aFGF-like reactivity associated with elongating lens cells was more intense and extensive. From the late lens vesicle stage (E14) to E18, reactivity in the lens was increasingly restricted to the equatorial regions which incorporate the germinative and transitional zones. From E16 to E18, aFGF-like reactivity in the retina was predominantly localised in the peripheral regions corresponding to the developing ciliary body and iris and in the central retina associated with ganglion cell axons. For bFGF, weak reactivity was detectable as early as E13 in the developing lens capsule and increased in intensity during lens development with the posterior capsule reacting more intensely than the anterior capsule. Retinal bFGF-like reactivity was first detected at E14, associated with differentiating ganglion cells in the central retina. From E16 to E18 the retinal ganglion cells showed increasing reactivity and the pattern of reactivity followed the centro-peripheral pattern of retinal development. Thus reactivity for aFGF is first detected in presumptive lens ectoderm and subsequently in optic vesicle cells which are closely associated with lens ectoderm. This raises the possibility that aFGF may be involved in inductive interactions between presumptive lens ectoderm and optic vesicle. Furthermore the localisation patterns established for both aFGF and bFGF during lens and retina morphogenesis suggest an important role for FGF in regulating their morphogenesis and growth.

Animals↗
PubMed2001

Predominant expression of fibroblast growth factor (FGF) 8, FGF4, and FGF receptor 1 in nonseminomatous and highly proliferative components of testicular germ cell tumors.

Nonseminomatous components within testicular germ cell tumors affect patient prognosis to varying degrees. These components are well known to mimic early embryonic totipotential tissues. Prompted by the recent observation that fibroblast growth factor (FGF) 8, FGF4, and FGF receptor (FGFR) 1 are required for the growth of early postimplantational embryonic tissues, we investigated the expressions of FGF8, FGF4, and FGFRI in surgically resected specimens of primary testicular germ cell tumors using an immunohistochemical method. All cases of embryonal carcinoma (14 cases), yolk sac tumor (3 cases), and choriocarcinoma (3 cases) showed positive immunostaining for FGF8, FGF4, and FGFR1. In contrast, out of 13 cases of seminoma, immunostaining was negative for FGF8, FGF4, and FGFR1 in 8 cases (61.5%), 6 cases (46.1%), and 7 cases (53.8%), respectively. In 7 cases of mature and immature teratoma, most areas showed negative immunostaining. In addition, the Ki-67 labeling index showed extremely high mitogenic activity in embryonal carcinoma, yolk sac tumor, and choriocarcinoma, which are precisely the carcinomas with the highest expressions of FGF8, FGF4, and FGFR1. It is in keeping with the immunohistochemical result that murine teratocarcinoma P19 cells were shown to express FGF8, FGF4, and FGFRI only under undifferentiated growth conditions. Taken together, these findings confirm the involvement of FGF8, FGF4, and FGFR1 in highly proliferative conditions of nonseminomatous germ cell tumors.

Adolescent↗
PubMed2006

Trk receptor binding and neurotrophin/fibroblast growth factor (FGF)-dependent activation of the FGF receptor substrate (FRS)-3.

We have investigated the signaling properties of the fibroblast growth factor (FGF) receptor substrate 3 (FRS3), also known as SNT-2 or FRS2beta, in neurotrophin-dependent differentiation in comparison with the related adapter FRS2 (SNT1 or FRS2alpha). We demonstrate that FRS3 binds all neurotrophin Trk receptor tyrosine kinases and becomes tyrosine phosphorylated in response to NGF, BDNF, NT-3 and FGF stimulation in transfected cells and/or primary cortical neurons. Second, the signaling molecules Grb2 and Shp2 bind FRS3 at consensus sites that are highly conserved among FRS family members and that Shp2, in turn, becomes tyrosine phosphorylated. While FRS3 over-expression in PC12 cells neither increases NGF-induced neuritogenesis nor activation of Map kinase/AKT, comparable to previous reports on FRS2, over-expression of a chimeric adapter containing the PH/PTB domains of the insulin receptor substrate (IRS) 2, in place of the PTB domain of FRS3 (IRS2-FRS3) supports insulin-dependent Map kinase activation and neurite outgrowth in PC12 cells. Collectively, these data demonstrate that FRS3 supports ligand-induced Map kinase activation and that the chimeric IRS2-FRS3 adapter is stimulating sufficient levels of activated MapK to support neurite outgrowth in PC12 cells.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Towards a resolution of the stoichiometry of the fibroblast growth factor (FGF)-FGF receptor-heparin complex.

The 22 members of the fibroblast growth factor (FGF) family have been implicated in cell proliferation, differentiation, survival, and migration. They are required for both development and maintenance of vertebrates, demonstrating an exquisite pattern of affinities for both protein and proteoglycan receptors. Recent crystal structures have suggested two models for the complex between FGFs, FGF receptors (FGFRs) and the proteoglycan heparan sulphate that mediates signalling, and have provided insight into how FGFs show differing affinities for the range of FGFRs. However, the physiological relevance of the two different models has not been made clear. Here, we demonstrate that the two complexes can be prepared from the same protein components, confirming that neither complex is the product of misfolded protein samples. Analyses of the complexes with mass spectrometry and analytical ultracentrifugation show that the species observed are consistent with the crystal structures formed using the two preparation protocols. This analysis supports the contention that both of the crystal structures reflect the state of the molecules in solution. Mass spectrometry of the complexes suggests that the stoichiometry of the complexes is 2 FGF1:2 FGFR2:1 heparin, regardless of the method used to prepare the complexes. These observations suggest that the two proposed complex architectures may both have relevance to the formation of an in vivo signalling complex, with a combination of the two interactions contributing to the formation of a larger focal complex.

Chromatography, Gel↗
PubMed2004

The crystal structure of fibroblast growth factor (FGF) 19 reveals novel features of the FGF family and offers a structural basis for its unusual receptor affinity.

The 22 members of the FGF family have been implicated in cell proliferation, differentiation, survival, and migration. They are required for both development and maintenance of vertebrates, demonstrating an exquisite pattern of affinities for both protein and proteoglycan receptors. FGF19, one of the most divergent human FGFs, is unique in binding solely to one receptor, FGFR4. We have used molecular replacement to solve the crystal structure of FGF19 at 1.3 A resolution using five superimposed FGF structures as the search model. The structure shows that two novel disulfide bonds found in FGF19, one of which appears to be conserved among several of the other FGFs, stabilize extended loops. The key heparin-binding loops of FGF19 have radically different conformations and charge patterns, compared to other FGFs, correlating with the unusually low affinity of FGF19 for heparin. A model for the complex of FGF19 with FGFR4 demonstrates that unique sequences in both FGF19 and FGFR4 are key to the formation of the complex. The structure therefore offers a clear explanation for the unusual affinity of FGF19 for FGFR4 alone.

Amino Acid Sequence↗
PubMed2006

Multimers of the fibroblast growth factor (FGF)-FGF receptor-saccharide complex are formed on long oligomers of heparin.

The minimal signalling unit for tyrosine kinase receptors is two protomers dimerized by one or more ligands. However, it is clear that maximal signalling requires the formation of larger complexes of many receptors at discrete foci on the cell surface. The biological interactions that lead to this are likely to be diverse and have system specific components. In the present study, we demonstrate that, in the FGF (fibroblast growth factor)-FGFR (FGF receptor) system, multimers of the minimal complex composed of two FGF1 and two FGFR2 protomers can form on a single chain of the co-receptor heparin. Using size-exclusion chromatography, we show that two complexes can form on heparin chains as small as 16 saccharide units. We also show by MS that discrete complexes containing exactly two copies of the minimal signalling unit are formed. However, the doublet of complexes appears to be less co-operative than the formation of the 2:2:1 FGF1:FGFR2:heparin complex, suggesting that this mechanism is one of a number of weaker interactions that might be involved in the formation of a focal complex on the cell surface.

Animals↗
PubMed2000

Synovial chondromatosis: the possible role of FGF 9 and FGF receptor 3 in its pathology.

Primary synovial chondromatosis (PSC) is a rare disorder of the synovium typified by cartilaginous nodule formation within the synovial membrane. Fibroblast growth factor receptor 3 (FGFR3) is a recently described specific marker of mesenchymal precartilaginous stem cells. Expression patterns of FGFR3 and its specific ligand, fibroblast growth factor 9 (FGF 9), were evaluated both in situ and in cell cultures. Histologically, cells at the periphery of the cartilage nodules express FGFR3 and PCNA (proliferating cell nuclear antigen). Elevated levels of FGF 9, its specific ligand, have been found in synovial fluids of patients with synovial chondromatosis. Synoviocytes but not chondrocytes from affected patients express FGF9 in culture. This pattern is absent in normal synovium and cartilage. Downregulation of FGF9 may provide a possible nonoperative therapy for PSC.

Cartilage, Articular↗
PubMed1998

Targeted disruption of fibroblast growth factor (FGF) receptor 2 suggests a role for FGF signaling in pregastrulation mammalian development.

We disrupted the fibroblast growth factor (FGF) receptor 2 (FGFR2) gene by introducing a neo cassette into the IIIc ligand binding exon and by deleting a genomic DNA fragment encoding its transmembrane domain and part of its kinase I domain. A recessive embryonic lethal mutation was obtained. Preimplantation development was normal until the blastocyst stage. Homozygous mutant embryos died a few hours after implantation at a random position in the uterine crypt, with collapsed yolk cavity. Mutant blastocysts hatched, adhered, and formed a layer of trophoblast giant cells in vitro, but after prolonged culture, the growth of the inner cell mass stopped, no visceral endoderm formed, and finally the egg cylinder disintegrated. It follows that FGFR2 is required for early postimplantation development between implantation and the formation of the egg cylinder. We suggest that FGFR2 contributes to the outgrowth, differentiation, and maintenance of the inner cell mass and raise the possibility that this activity is mediated by FGF4 signals transmitted by FGFR2. The role of early FGF signaling in pregastrulation development as a possible adaptation to mammalian (amniote) embryogenesis is discussed.

Animals↗
PubMed1995

Fibroblast growth factor (FGF) 3 from Xenopus laevis (XFGF3) binds with high affinity to FGF receptor 2.

We demonstrate that purified fibroblast growth factor (FGF) 3 from Xenopus laevis (XFGF3) activates the mitogen-activated protein kinase pathway and induces DNA synthesis in quiescent cells. To characterize the high affinity cell surface receptors that mediate these responses, the ligand binding domains of different FGF receptors (FGFR) were expressed on COS-1 cells, and their affinity for XFGF3 was determined. Unlabeled XFGF3 efficiently competed with 125I-FGF1 for binding to the IIIb and IIIc isoforms of FGFR2, giving 50% displacement (ID50) at 0.3-0.8 nM. Higher XFGF3 concentrations were needed to displace 125I-FGF1 from FGFR3 and FGFR1 (ID50 approximately 4 and 21 nM, respectively), indicating that XFGF3 has a lower affinity for these receptors. No association of XFGF3 with FGFR4 was found using this assay. FGFR2 isoforms isolated from both mouse and Xenopus showed similar high affinity binding of XFGF3 as determined by direct binding assays (Kd values in the range of 0.2-0.6 nM). These results indicate that the binding specificity of XFGF3 is different from that of other FGFs, and identifies FGFR2 as its high affinity receptor.

Amino Acid Sequence↗
PubMed2005

Fibroblast growth factor (FGF) 18 signals through FGF receptor 3 to promote chondrogenesis.

Signaling by fibroblast growth factor (FGF) 18 and FGF receptor 3 (FGFR3) have been shown to regulate proliferation, differentiation, and matrix production of articular and growth plate chondrocytes in vivo and in vitro. Notably, the congenital absence of either FGF18 or FGFR3 resulted in similar expansion of the growth plates of fetal mice and the addition of FGF18 to human articular chondrocytes in culture enhanced proliferation and matrix production. Based on these and other experiments it has been proposed that FGF18 signals through FGFR3 to promote cartilage production by chondrocytes. Its role in chondrogenesis remains to be defined. In the current work we used the limb buds of FGFR3(+/+) and FGFR3(-/-) embryonic mice as a source of mesenchymal cells to determine how FGF18 signaling affects chondrogenesis. Confocal laser-scanning microscopy demonstrated impaired cartilage nodule formation in the FGFR3(-/-) cultures. Potential contributing factors to the phenotype were identified as impaired mitogenic response to FGF18, decreased production of type II collagen and proteoglycan in response to FGF18 stimulation, impaired interactions with the extracellular matrix resulting from altered integrin receptor expression, and altered expression of FGFR1 and FGFR2. The data identified FGF18 as a selective ligand for FGFR3 in limb bud mesenchymal cells, which suppressed proliferation and promoted their differentiation and production of cartilage matrix. This work, thus, identifies FGF18 and FGFR3 as potential molecular targets for intervention in tissue engineering aimed at cartilage repair and regeneration of damaged cartilage.

Animals↗