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PubMed2000

Trk1 and Trk2 define the major K(+) transport system in fission yeast.

The trk1(+) gene has been proposed as a component of the K(+) influx system in the fission yeast Schizosaccharomyces pombe. Previous work from our laboratories revealed that trk1 mutants do not show significantly altered content or influx of K(+), although they are more sensitive to Na(+). Genome database searches revealed that S. pombe encodes a putative gene (designated here trk2(+)) that shows significant identity to trk1(+). We have analyzed the characteristics of potassium influx in S. pombe by using trk1 trk2 mutants. Unlike budding yeast, fission yeast displays a biphasic transport kinetics. trk2 mutants do not show altered K(+) transport and exhibit only a slightly reduced Na(+) tolerance. However, trk1 trk2 double mutants fail to grow at low K(+) concentrations and show a dramatic decrease in Rb(+) influx, as a result of loss of the high-affinity transport component. Furthermore, trk1 trk2 cells are very sensitive to Na(+), as would be expected for a strain showing defective potassium transport. When trk1 trk2 cells are maintained in K(+)-free medium, the potassium content remains higher than that of the wild type or trk single mutants. In addition, the trk1 trk2 strain displays increased sensitivity to hygromycin B. These results are consistent with a hyperpolarized state of the plasma membrane. An additional phenotype of cells lacking both Trk components is a failure to grow at acidic pH. In conclusion, the Trk1 and Trk2 proteins define the major K(+) transport system in fission yeast, and in contrast to what is known for budding yeast, the presence of any of these two proteins is sufficient to allow growth at normal potassium levels.

Amino Acid Sequence↗

PubMed1985

Genetic analysis of developmental mechanisms in hydra. XVI. Effect of food on budding and developmental gradients in a mutant strain L4.

Effect of food was examined on the budding rate and the developmental gradients of a mutant hydra strain L4. This mutant strain has very high levels of head-inhibition potential gradient along its body axis (Takano & Sugiyama, 1983). It also has a reduced budding capacity when it is cultured using brine shrimp nauplii as food, but its budding capacity is significantly improved when a small amount of tubifex worm tissue is added to its diet of brine shrimp (Takano, 1984). To test whether or not this change of budding rate is correlated with the change in the levels of the head-activation or head-inhibition potential gradients, L4 animals were cultured on the diet of brine shrimp with or without addition of tubifex worm tissue and the budding rates and the gradient levels were examined in these animals. The results showed that food affected the budding rate in L4 without affecting its gradient levels. This suggests that the gradient levels and the budding rate in L4 are are uncorrelated to each other, and that therefore the high levels of head-inhibition potential are not the cause for the low budding rate in this strain (cf., Takano & Sugiyama, 1983).

Animals↗

PubMed1994

Positioning of cell growth and division after osmotic stress requires a MAP kinase pathway.

The yeast Saccharomyces cerevisiae has a genetic program for selecting and assembling a bud site on the cell cortex. Yeast cells confine their growth to the emerging bud, a process directed by cortical patches of actin filaments within the bud. We have investigated how cells regulate budding in response to osmotic stress, focusing on the role of the high osmolarity glycerol response (HOG) pathway in mediating this regulation. An increase in external osmolarity induces a growth arrest in which actin filaments are lost from the bud. This is followed by a recovery phase in which actin filaments return to their original locations and growth of the original bud resumes. After recovery from osmotic stress, haploid cells retain an axial pattern of bud site selection while diploids change their bipolar budding pattern to an increased bias for forming a bud on the opposite side of the cell from the previous bud site. Mutants lacking the mitogen-activated protein (MAP) kinase encoded by HOG1 or the MAP kinase kinase encoded by PBS2 (previously HOG4) show a similar growth arrest after osmotic stress. However, in the recovery phase, the mutant cells (a) do not restart growth of the original bud but rather start a new bud, (b) fail to restore actin filaments to the original bud but move them to the new one, and (c) show a more random budding pattern. These defects are elicited by an increase in osmolarity and not by other environmental stresses (e.g., heat shock or change in carbon source) that also cause a temporary growth arrest and shift in actin distribution. Thus, the HOG pathway is required for repositioning of the actin cytoskeleton and the normal spatial patterns of cell growth after recovery from osmotic stress.

Actins↗

PubMed1992

Dual cell cycle checkpoints sensitive to chromosome replication and DNA damage in the budding yeast Saccharomyces cerevisiae.

In eucaryotic cells chromosomes must be fully replicated and repaired before mitosis begins. Genetic studies indicate that this dependence of mitosis on completion of DNA replication and DNA repair derives from a negative control called a checkpoint which somehow checks for replication and DNA damage and blocks cell entry into mitosis. Here we summarize our current understanding of the genetic components of the cell cycle checkpoint in budding yeast. Mutants were identified and their phase and signal specificity tested primarily through interactions of the arrest-defective mutants with cell division cycle mutants. The results indicate that dual checkpoint controls exist in budding yeast, one control sensitive to inhibition of DNA replication (S-phase checkpoint), and a distinct but overlapping control sensitive to DNA repair (G2 checkpoint). Six genes are required for arrest in G2 phase after DNA damage (RAD9, RAD17, RAD24, MEC1, MEC2, and MEC3), and two of these are also essential for arrest in S phase when DNA replication is blocked (MEC1 and MEC2).

Cell Cycle↗

PubMed1986

Experimental manipulation leading to induction of dorsal ectodermal ridges on normal limb buds results in a phenocopy of the Eudiplopodia chick mutant.

Elongation of chick limb buds depends on the presence of the apical ectodermal ridge which is induced by subjacent limb bud mesoderm. Recombination experiments have shown that the limb bud mesoderm loses the capacity to induce ridges by late stage 17. Moreover, in normal limb development only one ridge forms. However, in the eudiplopodia chick mutant accessory ectodermal ridges form on the dorsal surface of limb buds as late as stage 22. Tissue recombinant experiments show that the mutation affects the ectoderm, extending the time it responds to ridge induction (R.A. Fraser and U.K. Abbott (1971). J. Exp. Zool. 176, 237-248) while the mesoderm is normal. The result is polydactyly, with extra digits dorsal to the normal digits. Because eudiplopodia limb bud dorsal mesoderm can induce ridges at stage 22 but is unaffected by the gene, genetically normal dorsal limb bud mesoderm may also be able to induce ridges after stage 17. To test this possibility we grafted stages 14-18 flank ectoderm to normal limb bud dorsal mesoderm and found that mesoderm from stages 17 through 20 was able to induce a ridge and subsequently dorsal digits developed. Limbs with duplicate digits were similar to eudiplopodia limbs. In other experiments, stage 18, 19, and 20 leg bud dorsal ectoderm did not form ridges when grafted to leg bud dorsal mesoderm of the same stage, indicating a lack of response to the mesoderm. Finally, the inductive capacity of limb bud mesoderm appeared to be reduced compared to mesoderm at pre-limb bud stages. These experiments demonstrate a spatially generalized potential in limb bud dorsal mesoderm to induce ridges during the stages when the apical ridge is induced. The determination of where the ridge will form and the acquired inability of limb bud dorsal ectoderm to respond to induction by underlying mesoderm are necessary early pattern forming events which assure that a single proximodistal limb axis will form.

Animals↗

PubMed2004

Morphological features of tail bud development in truncate mouse mutants.

A key malformation in the homozygous truncate mouse mutants is a partial lack of the notochord in the embryo tail. In order to analyze if tail bud development was affected by the truncate (tc) mutation, serial semithin sections of tails of the homozygous mutant embryos were compared to the wild-type controls. In the wild-type embryos morphologically uniform mesenchyme of the tail bud was continuous via the medullary cord to the secondary neural tube, and via the tail cord to the notochord and the gut. In truncate embryos the tail cord was not continuous to the notochord, but to the additional lumen of the tail gut resulting in tail gut duplication. Toward the base of the tail two tail guts subsequently fused together or the additional one disappeared. If present in the tip of the tail, the notochord in truncate embryos ended near the ventral border of the secondary neural tube. The rest of the tail notochord was fragmented and the posterior ends of the fragments were frequently adjacent or even continuous to the neural tube. We suggest that the improper regionalization of the tail bud, where notochord is associated with the neural tube rather than with the tail gut, is related to the subsequent segmental lack of the notochord in truncate mutants.

Animals↗

PubMed1997

A small conserved domain in the yeast Spa2p is necessary and sufficient for its polarized localization.

SPA2 encodes a yeast protein that is one of the first proteins to localize to sites of polarized growth, such as the shmoo tip and the incipient bud. The dynamics and requirements for Spa2p localization in living cells are examined using Spa2p green fluorescent protein fusions. Spa2p localizes to one edge of unbudded cells and subsequently is observable in the bud tip. Finally, during cytokinesis Spa2p is present as a ring at the mother-daughter bud neck. The bud emergence mutants bem1 and bem2 and mutants defective in the septins do not affect Spa2p localization to the bud tip. Strikingly, a small domain of Spa2p comprised of 150 amino acids is necessary and sufficient for localization to sites of polarized growth. This localization domain and the amino terminus of Spa2p are essential for its function in mating. Searching the yeast genome database revealed a previously uncharacterized protein which we name, Sph1p (a2p omolog), with significant homology to the localization domain and amino terminus of Spa2p. This protein also localizes to sites of polarized growth in budding and mating cells. SPH1, which is similar to SPA2, is required for bipolar budding and plays a role in shmoo formation. Overexpression of either Spa2p or Sph1p can block the localization of either protein fused to green fluorescent protein, suggesting that both Spa2p and Sph1p bind to and are localized by the same component. The identification of a 150-amino acid domain necessary and sufficient for localization of Spa2p to sites of polarized growth and the existence of this domain in another yeast protein Sph1p suggest that the early localization of these proteins may be mediated by a receptor that recognizes this small domain.

Amino Acid Sequence↗

PubMed2006

Differential regulation of gene expression in the digit forming area of the mouse limb bud by SHH and gremlin 1/FGF-mediated epithelial-mesenchymal signalling.

Spatially and temporally coordinated changes in gene expression are crucial to orderly progression of embryogenesis. We combine mouse genetics with experimental manipulation of signalling to analyze the kinetics by which the SHH morphogen and the BMP antagonist gremlin 1 (GREM1) control gene expression in the digit-forming mesenchyme of mouse limb buds. Although most mesenchymal cells respond rapidly to SHH signalling, the transcriptional upregulation of specific SHH target signals in the mesenchyme occurs with differential temporal kinetics and in a spatially restricted fashion. In particular, the expression of the BMP antagonist Grem1 is always upregulated in mesenchymal cells located distal to the SHH source and acts upstream of FGF signalling by the apical ectodermal ridge. GREM1/FGF-mediated feedback signalling is, in turn, required to propagate SHH and establish the presumptive digit expression domains of the Notch ligand jagged 1 (Jag1) and 5'Hoxd genes in the distal limb bud mesenchyme. Their establishment is significantly delayed in Grem1-deficient limb buds and cannot be rescued by specific restoration of SHH signalling in mutant limb buds. This shows that GREM1/FGF feedback signalling is required for regulation of the temporal kinetics of the mesenchymal response to SHH signalling. Finally, inhibition of SHH signal transduction at distinct time points reveals the differential temporal dependence of Grem1, Jag1 and 5'Hoxd gene expression on SHH signalling. In particular, the expression of Hoxd13 depends on SHH signal transduction significantly longer than does Hoxd11 expression, revealing that the reverse co-linear establishment, but not maintenance of their presumptive digit expression domains, depends on SHH signalling.

Animals↗

PubMed1996

Gene expression in the limbless mutant: polarized gene expression in the absence of Shh and an AER.

Limb buds in the limbless chick begin to form normally but fail to form an AER and ultimately degenerate. Wnt7a and LMX-1, which are restricted to the dorsal half of a normal limb bud, are expressed throughout the ectoderm and mesenchyme of the mutant buds, respectively. Engrailed-1, normally expressed in ventral limb ectoderm, is not expressed in the limbless bud. This defect precedes the normal period of AER formation and no localized expression of genes normally found in the AER is observed in limbless buds. Consistent with the lack of molecular specialization of an AER, Shh and BMP-2 are not expressed in the ZPA of the mutant bud. Despite the lack of Shh, FGF-4, or BMP-2 expression, the hoxd genes are expressed at low levels in the posterior mesenchyme of the bud. Forced expression of Shh fails to rescue the positive feedback loop between the AER and the ZPA and does not lead to distal outgrowth. However, Shh does maintain the part of the bud formed during pre-AER stages. These results support the importance of the dorsal/ventral boundary in the initiation of AER formation and imply that Shh is not required for the initial activation of polarized hoxd gene expression during limb development.

Animals↗

PubMed1991

legless insertional mutation: morphological, molecular, and genetic characterization.

Limb morphogenesis is an excellent model system to study pattern formation during vertebrate development. The legless (lgl) insertional mutation can serve as a tool to analyze specific events in limb development at the embryologic, genetic, and molecular levels. Hemizygous mice of this transgenic line are phenotypically normal, but homozygous mutants are inviable and exhibit limb, brain, and craniofacial malformations, as well as situs inversus. By morphological analysis of mutant hindlimb buds we show absence of a normal apical ectodermal ridge, a structure required for limb bud outgrowth, and an unusually high degree of mesenchymal and ectodermal cell death. Mutant embryos are extremely sensitive to retinoic acid, a known teratogen with a proposed role in limb development. The hindlimb malformations in legless mutants are less severe when bred into the BALB/c background, suggesting the involvement of other strain-specific genes. Molecular analysis of the disrupted region indicates two tightly linked insertion sites. Sequences flanking the transgene insertions have been cloned and mapped to chromosome 12, near the iv (situs inversus viscerum) locus. Consistent with this, complementation tests confirm allelism of lgl and iv and suggest that the transgene insertion may have disrupted more than one gene. Phylogenetically conserved sequences flanking the transgene insertions were identified and used to isolate candidate lgl and iv cDNAs.

Alleles↗

PubMed1975

Cell movement and adhesion in the developing chick wing bud: studies on cultured mesenchyme cells from normal and talpid mutant embryos.

Mesenchyme fragments from early wing buds of normal and talpid3 mutant chick embryos were explanted for culture in plastic Petri dishes and the behaviour of individual cells as they moved out on to the plastic surface was studied by time-lapse ciné photography, followed by statistical analysis. Two parameters of cell movement were recorded: (1) the distances moved over measured 100-s intervals and (2) the length of time each cell spent at rest before moving on. The average speed of movement over the whole path tracked for each cell, inclusive of time at rest, was significantly greater in normal than talpid3 cells. There was no significant difference between normal and mutant cells in the average distance mover per 100-s step, equivalent to the speed over the whole path exclusive of time at rest, but the percentage of time spent at rest was significantly less in normal than in talpid3 cells. This difference appears to be related to a difference in cell morphology, since it was observed that the mutant cells were more flattened than normals, with very extensive ruffled membranes and short spiky microvilli all round the cell periphery. The relation of these differences in cell morphology and behaviour in vitro to the production of the characteristically fan-shaped limb bud outgrowth and altered pattern of cartilage elements in the developing mutant limb bud is discussed.

Animals↗

PubMed2000

Polarized growth controls cell shape and bipolar bud site selection in Saccharomyces cerevisiae.

We examined the relationship between polarized growth and division site selection, two fundamental processes important for proper development of eukaryotes. Diploid Saccharomyces cerevisiae cells exhibit an ellipsoidal shape and a specific division pattern (a bipolar budding pattern). We found that the polarity genes SPA2, PEA2, BUD6, and BNI1 participate in a crucial step of bud morphogenesis, apical growth. Deleting these genes results in round cells and diminishes bud elongation in mutants that exhibit pronounced apical growth. Examination of distribution of the polarized secretion marker Sec4 demonstrates that spa2Delta, pea2Delta, bud6Delta, and bni1Delta mutants fail to concentrate Sec4 at the bud tip during apical growth and at the division site during repolarization just prior to cytokinesis. Moreover, cell surface expansion is not confined to the distal tip of the bud in these mutants. In addition, we found that the p21-activated kinase homologue Ste20 is also important for both apical growth and bipolar bud site selection. We further examined how the duration of polarized growth affects bipolar bud site selection by using mutations in cell cycle regulators that control the timing of growth phases. The grr1Delta mutation enhances apical growth by stabilizing G(1) cyclins and increases the distal-pole budding in diploids. Prolonging polarized growth phases by disrupting the G(2)/M cyclin gene CLB2 enhances the accuracy of bud site selection in wild-type, spa2Delta, and ste20Delta cells, whereas shortening the polarized growth phases by deleting SWE1 decreases the fidelity of bipolar budding. This study reports the identification of components required for apical growth and demonstrates the critical role of polarized growth in bipolar bud site selection. We propose that apical growth and repolarization at the site of cytokinesis are crucial for establishing spatial cues used by diploid yeast cells to position division planes.

Cell Cycle↗

PubMed2006

Budding yeast DNA damage adaptation mutants exhibit defects in mitotic exit.

In the presence of double strand breaks, DNA damage checkpoint halts cell cycle progression. However, cells ultimately escape the checkpoint arrest and reenter cell cycle in the presence of irreparable DNA damage. cdc5-ad was identified as a mutant that fails to adapt to the cell cycle arrest induced by DNA damage checkpoint. In budding yeast, Cdc5 protein kinase is a component of both MEN and FEAR pathways that are required for mitotic exit. It remains unclear whether the adaptation defect of cdc5-ad mutant cells is related to the function of Cdc5 in mitotic exit. Here we present evidence indicating that cdc5-ad mutant cells exhibit defects in mitotic exit. cdc5-ad mutant cells are sensitive to high dosage of Amn1, a negative regulator of MEN. It also shows synthetic growth defects with mutants in MEN pathway. Moreover, mutants in FEAR pathway exhibit defects in DNA damage adaptation. Thus, we conclude that the compromised mitotic exit pathway contributes to DNA damage adaptation defects in cdc5-ad mutant cells.

Adaptation, Physiological↗

PubMed2000

Severe limb defects in Hypodactyly mice result from the expression of a novel, mutant HOXA13 protein.

Hypodactyly (Hoxa13(Hd)) mice have a 50-bp deletion in the coding region of exon 1 of the Hoxa13 gene and have more severe limb defects than mice with an engineered deletion of the entire gene (Hoxa13(-/-)). Increased cell death is observed in the autopod of Hoxa13(Hd/Hd) but not Hoxa13(-/-) limb buds. In addition, compound heterozygotes for one Hd allele and a Hoxa13(-) allele have a more severe limb phenotype than mice homozygous for the engineered null allele, suggesting a dominant-negative effect of the Hd mutation. The Hoxa13(Hd) deletion does not interfere with steady-state mRNA levels; however, its consequences on translation are unknown. In this paper, we characterize the Hoxa13 transcription initiation site in limbs and determine the initiator methionine of HOXA13. We show that the Hoxa13(Hd) deletion results in a translational frame shift that leads to the loss of wild-type HOXA13 protein and the simultaneous production of a novel, stable protein in the limb buds of mutant mice. The mutant Hd protein (HOXA13(Hd)) consists of the first 25 amino acids of wild-type HOXA13 sequence, followed by 275 amino acids of arginine- and lysine-rich, novel sequence, and lacks the homeodomain. Like wild-type HOXA13, HOXA13(Hd) is localized to the nucleus in transfected COS-7 cells, perhaps mediated by the arginine- and lysine-rich peptide sequences created by the translational frame shift. To determine whether HOXA13(Hd) could alter limb morphogenesis, we misexpressed the mutant mRNA throughout the developing limb bud using a Prx-1 promoter-Hd gene construct in transgenic mice. Three of 15 transgenic founder animals displayed reduction or absence of proximal and distal limb structures. We propose that the expression of HOXA13(Hd) plays a role in the profound failure of digit formation in Hoxa13(Hd/Hd) mice and explains the morphologic differences between these two Hoxa13 alleles.

Animals↗

PubMed1999

Constitutive activation of sonic hedgehog signaling in the chicken mutant talpid(2): Shh-independent outgrowth and polarizing activity.

We have examined the developmental properties of the polydactylous chicken mutant, talpid(2). Ptc, Gli1, Bmp2, Hoxd13, and Fgf4 are expressed throughout the anteroposterior axis of the mutant limb bud, despite normal Shh expression. The expression of Gli3, Ihh, and Dhh appears to be normal, suggesting that the Shh signaling pathway is constitutively active in talpid(2) mutants. We show that preaxial talpid(2) limb bud mesoderm has polarizing activity in the absence of detectable Shh mRNA. When the postaxial talpid(2) limb bud (including all Shh-expressing cells) is removed, the preaxial cells reform a normal-shaped talpid(2) limb bud (regulate). However, a Shh-expressing region (zone of polarizing activity) does not reform; nevertheless Fgf4 expression in the apical ectodermal ridge is maintained. Such reformed talpid(2) limb buds develop complete talpid(2) limbs. After similar treatment, normal limb buds downregulate Fgf4, the preaxial cells do not regulate, and a truncated anteroposterior deficient limb forms. In talpid(2) limbs, distal outgrowth is independent of Shh and correlates with Fgf4, but not Fgf8, expression by the apical ectodermal ridge. We propose a model for talpid(2) in which leaky activation of the Shh signaling pathway occurs in the absence of Shh ligand.

Animals↗

PubMed1997

Mutational analysis of Cak1p, an essential protein kinase that regulates cell cycle progression.

In Saccharomyces cerevisiae, entry into S phase requires the activation of the protein kinase Cdc28p through binding with cyclin Clb5p or Clb6p, as well as the destruction of the cyclin-dependent kinase inhibitor Sic1p. Mutants that are defective in this activation event arrest after START, with unreplicated DNA and multiple, elongated buds. These mutants include cells defective in CDC4, CDC34 or CDC53, as well as cells that have lost all CLB function. Here we describe mutations in another gene, CAK1, that lead to a similar arrest. Cells that are defective in CAK1 are inviable and arrest with a single nucleus and multiple, elongated buds. CAK1 encodes a protein kinase most closely related to the Cdc2p family of protein kinases. Mutations that lead to the production of an inactive kinase that can neither autophosphorylate, nor phosphorylate Cdc28p in vitro are also incapable of rescuing a cell with a deletion of CAK1. These results underscore the importance of the Cak1p protein kinase activity in cell cycle progression.

Amino Acid Sequence↗

PubMed1984

Genetic analysis of developmental mechanisms in hydra. IX. Effect of food on development of a slow-budding strain (L4).

A mutant hydra strain L4 produces buds at a much lower rate than the standard wild-type strain (105) when fed with brine shrimp nauplii (T. Sugiyama and T. Fujisawa, 1979b, Dev. Growth Differ. 21, 361-375). It was found that addition of a small amount of tubifex worm tissue to the normal brine shrimp diet significantly improved the budding rate of L4 but not of 105. Detailed examination and comparison of food effect on various developmental processes in L4 and 105 have provided the following observations. (1) L4 development is strongly affected by food and has significantly lower rates than 105 in all the developmental parameters examined which involve the bud initiation process. In contrast, such effects and differences are not observed in parameters not involving bud initiation. These observations suggest that L4 has a defect(s) in its bud initiating mechanisms and that the expression of this defect is somehow strongly affected by food. (2) Epithelial cells proliferate in L4 nearly as rapidly as in 105 and without food effect. Epithelial cells produced by cell division are mostly utilized to form buds in mature 105 polyps. These cells, however, are not fully utilized for this purpose in L4 polyps which bud very slowly. Instead, they appear to be somehow lost from tissue in these animals.

Animals↗

PubMed1999

Signal relay by BMP antagonism controls the SHH/FGF4 feedback loop in vertebrate limb buds.

Outgrowth and patterning of the vertebrate limb are controlled by reciprocal interactions between the posterior mesenchyme (polarizing region) and a specialized ectodermal structure, the apical ectodermal ridge (AER). Sonic hedgehog (SHH) signalling by the polarizing region modulates fibroblast growth factor (FGF)4 signalling by the posterior AER, which in turn maintains the polarizing region (SHH/FGF4 feedback loop). Here we report that the secreted bone-morphogenetic-protein (BMP) antagonist Gremlin relays the SHH signal from the polarizing region to the AER. Mesenchymal Gremlin expression is lost in limb buds of mouse embryos homozygous for the limb deformity (Id) mutation, which disrupts establishment of the SHH/FGF4 feedback loop. Grafting Gremlin-expressing cells into ld mutant limb buds rescues Fgf4 expression and restores the SHH/FGF4 feedback loop. Analysis of Shh-null mutant embryos reveals that SHH signalling is required for maintenance of Gremlin and Formin (the gene disrupted by the ld mutations). In contrast, Formin, Gremlin and Fgf4 activation are independent of SHH signalling. This study uncovers the cascade by which the SHH signal is relayed from the posterior mesenchyme to the AER and establishes that Formin-dependent activation of the BMP antagonist Gremlin is sufficient to induce Fgf4 and establish the SHH/FGF4 feedback loop.

Animals↗