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Precise control of morphogen signaling levels is essential for proper development. An outstanding question is: what mechanisms ensure proper morphogen activity and correct cellular responses? Previous work has identified Semaphorin (SEMA) receptors, Neuropilins (NRPs) and Plexins (PLXNs), as positive regulators of the Hedgehog (HH) signaling pathway. Here, we provide evidence that NRPs and PLXNs antagonize Wnt signaling in both fibroblasts and epithelial cells. Further, Nrp1/2 deletion in fibroblasts results in elevated baseline Wnt pathway activity and increased maximal responses to Wnt stimulation. Notably, and in contrast to HH signaling, SEMA receptor-mediated Wnt antagonism is independent of primary cilia. Mechanistically, PLXNs and NRPs act downstream of Dishevelled (DVL) to destabilize ß-catenin (CTNNB1) in a proteosome-dependent manner. Further, NRPs, but not PLXNs, act in a GSK3ß/CK1-dependent fashion to antagonize Wnt signaling, suggesting distinct repressive mechanisms for these SEMA receptors. Overall, this study identifies SEMA receptors as novel Wnt pathway antagonists that may also play larger roles integrating signals from multiple inputs.
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The Hedgehog (HH) pathway regulates embryonic development of anterior tongue taste fungiform papilla (FP) and the posterior circumvallate (CVP) and foliate (FOP) taste papillae. HH signaling also mediates taste organ maintenance and regeneration in adults. However, there are knowledge gaps in HH pathway component expression during postnatal taste organ differentiation and maturation. Importantly, the HH transcriptional effectors GLI1, GLI2 and GLI3 have not been investigated in early postnatal stages; the HH receptors PTCH1, GAS1, CDON and HHIP, required to either drive HH pathway activation or antagonism, also remain unexplored. Using lacZ reporter mouse models, we mapped expression of the HH ligand SHH, HH receptors, and GLI transcription factors in FP, CVP and FOP in early and late postnatal and adult stages. In adults we also studied the soft palate, and the geniculate and trigeminal ganglia, which extend afferent fibers to the anterior tongue. Shh and Gas1 are the only components that were consistently expressed within taste buds of all three papillae and the soft palate. In the first postnatal week, we observed broad expression of HH signaling components in FP and adjacent, non-taste filiform (FILIF) papillae in epithelium or stroma and tongue muscles. Notably, we observed elimination of Gli1 in FILIF and Gas1 in muscles, and downregulation of Ptch1 in lingual epithelium and of Cdon, Gas1 and Hhip in stroma from late postnatal stages. Further, HH receptor expression patterns in CVP and FOP epithelium differed from anterior FP. Among all the components, only known positive regulators of HH signaling, SHH, Ptch1, Gli1 and Gli2, were expressed in the ganglia. Our studies emphasize differential regulation of HH signaling in distinct postnatal developmental periods and in anterior versus posterior taste organs, and lay the foundation for functional studies to understand the roles of numerous HH signaling components in postnatal tongue development.
Assuntos
Proteínas Hedgehog , Transdução de Sinais , Papilas Gustativas , Língua , Animais , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/genética , Língua/metabolismo , Língua/crescimento & desenvolvimento , Camundongos , Papilas Gustativas/metabolismo , Papilas Gustativas/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento , Homeostase , Receptor Patched-1/metabolismo , Receptor Patched-1/genética , Proteína GLI1 em Dedos de Zinco/metabolismo , Proteína GLI1 em Dedos de Zinco/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Proteína Gli2 com Dedos de Zinco/metabolismo , Proteína Gli2 com Dedos de Zinco/genética , Proteína Gli3 com Dedos de Zinco/metabolismo , Proteína Gli3 com Dedos de Zinco/genética , Proteínas do Tecido Nervoso , Proteínas de Ciclo Celular , Proteínas Ligadas por GPIRESUMO
While the kinesin-2 motors KIF3A and KIF3B have essential roles in ciliogenesis and Hedgehog (HH) signal transduction, potential role(s) for another kinesin-2 motor, KIF17, in HH signaling have yet to be explored. Here, we investigated the contribution of KIF17 to HH-dependent cerebellar development, where Kif17 is expressed in both HH-producing Purkinje cells and HH-responding cerebellar granule neuron progenitors (CGNPs). Germline Kif17 deletion in mice results in cerebellar hypoplasia due to reduced CGNP proliferation, a consequence of decreased HH pathway activity mediated through decreased Sonic HH (SHH) protein. Notably, Purkinje cell-specific Kif17 deletion partially phenocopies Kif17 germline mutants. Unexpectedly, CGNP-specific Kif17 deletion results in the opposite phenotype-increased CGNP proliferation and HH target gene expression due to altered GLI transcription factor processing. Together, these data identify KIF17 as a key regulator of HH-dependent cerebellar development, with dual and opposing roles in HH-producing Purkinje cells and HH-responding CGNPs.
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Cerebelo , Cerebelo/anormalidades , Proteínas Hedgehog , Cinesinas , Malformações do Sistema Nervoso , Células de Purkinje , Animais , Cinesinas/metabolismo , Cinesinas/genética , Cerebelo/metabolismo , Cerebelo/crescimento & desenvolvimento , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/genética , Camundongos , Células de Purkinje/metabolismo , Transdução de Sinais , Proliferação de Células , Camundongos Knockout , Regulação da Expressão Gênica no Desenvolvimento , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/citologia , Proteína GLI1 em Dedos de Zinco/metabolismo , Proteína GLI1 em Dedos de Zinco/genética , Deficiências do DesenvolvimentoRESUMO
Threatened species throughout the world are in decline due to various causes. In some cases, predators of conservation or cultural value are causing the decline of threatened prey, presenting a conservation conundrum for managers. We surveyed marine turtle nests on K'gari (formally known as Fraser Island), Australia, to investigate dingo predation of green and loggerhead turtle nests, where each of these species is of conservation value. Our monitoring revealed that 84% of nests were predated by dingoes. Only 16% of nests were not consumed by dingoes, and only 5.7% of nests were confirmed to have successfully hatched. Up to 94% of nests were consumed in some areas, and predation rates were similar across different dingo packs. Information on the available numbers of nests and dingoes in the area indicated that turtle nests alone are sufficient to support extant dingoes over the summer. These results indicate that marine turtle eggs represent a previously unquantified but important food source for dingoes on K'gari, and that turtle nests at this rookery site are under serious threat from dingoes. This research should highlight the importance of prioritising the protection of turtle nests from dingoes or risk losing the entire rookery forever in the near future.
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Aversive geofencing devices (AGDs) or animal-borne satellite-linked shock collars might become a useful tool to mitigate human-elephant conflict (HEC). AGDs have the potential to condition problem elephants to avoid human-dominated landscapes by associating mild electric shocks with preceding audio warnings given as they approach virtual boundaries. We assessed the opinions of different stakeholders (experts, farmers, and others who have and have not experienced HEC; n = 611) on the potential use of AGDs on Asian elephants. Most respondents expressed positive opinions on the potential effectiveness of AGDs in managing elephant movement (62.2%). About 62.8% respondents also provided positive responses for the acceptability of AGDs if pilot studies with captive elephants have been successful in managing their movements. Some respondents perceived AGDs to be unacceptable because they are unethical or harmful and would be unsuccessful given wild elephants may respond differently to AGDs than captive elephants. Respondents identified acceptability, support and awareness of stakeholders, safety and wellbeing of elephants, logistical difficulties, durability and reliable functionality of AGDs, and uncertainties in elephants' responses to AGDs as potential challenges for implementing AGDs. These issues need attention when developing AGDs to increase support from stakeholders and to effectively reduce HEC incidents in the future.
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Killing animals has been a ubiquitous human behaviour throughout history, yet it is becoming increasingly controversial and criticised in some parts of contemporary human society. Here we review 10 primary reasons why humans kill animals, discuss the necessity (or not) of these forms of killing, and describe the global ecological context for human killing of animals. Humans historically and currently kill animals either directly or indirectly for the following reasons: (1) wild harvest or food acquisition, (2) human health and safety, (3) agriculture and aquaculture, (4) urbanisation and industrialisation, (5) invasive, overabundant or nuisance wildlife control, (6) threatened species conservation, (7) recreation, sport or entertainment, (8) mercy or compassion, (9) cultural and religious practice, and (10) research, education and testing. While the necessity of some forms of animal killing is debatable and further depends on individual values, we emphasise that several of these forms of animal killing are a necessary component of our inescapable involvement in a single, functioning, finite, global food web. We conclude that humans (and all other animals) cannot live in a way that does not require animal killing either directly or indirectly, but humans can modify some of these killing behaviours in ways that improve the welfare of animals while they are alive, or to reduce animal suffering whenever they must be killed. We encourage a constructive dialogue that (1) accepts and permits human participation in one enormous global food web dependent on animal killing and (2) focuses on animal welfare and environmental sustainability. Doing so will improve the lives of both wild and domestic animals to a greater extent than efforts to avoid, prohibit or vilify human animal-killing behaviour.
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Animais Domésticos , Animais Selvagens , Animais , Humanos , Bem-Estar do Animal , Agricultura , Espécies em Perigo de ExtinçãoRESUMO
Humans and dingoes (Canis familiaris (dingo)) share the environment of K'gari, and conflict inevitably occurs between the two species, particularly over food. Dingo attacks on humans have occurred, and some have been serious and even fatal in outcome. Wildlife feeding may cause animals to develop unnatural and potentially dangerous behaviours towards conspecifics and humans on a relatively frequent basis. Food-based attraction has been implicated in the development of human-directed aggression in the dingo population of K'gari. Supplemental feeding, whether intentional or accidental, alters wildlife foraging behaviours and may have consequences at the population and ecosystem levels. Management strategies such as education programs, prohibition of inappropriate human behaviours (compliance) and fencing of garbage dumps have each been implemented to stop the intentional or inadvertent feeding of dingoes by people. However, there has been no formal assessment of the effectiveness of these interventions at reducing food-related dingo-human incidents over time. We collated and analysed 7791 unique reports of dingo-human interactions on K'gari between 1990 and 2020, inclusive of 1307 food-related reports, including the severity of these interactions. These data showed clear seasonal peaks in the percentage of food-related dingo-human interactions, corresponding with biologically significant breeding periods in autumn and weaning and dispersing in spring. Trends in serious food-related incidents remained stable overtime. Less serious food-related incidents declined, suggesting that management efforts were successful. However, these efforts appear to have reached the limits of their effectiveness. Further innovations are required to reduce serious incidents involving the relatively few dingoes and people still experiencing conflict, and thereby provide protection to both species on K'gari.
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Developing Future Biologists (DFB) is an inclusive, trainee-run organization that strives to excite and engage the next generation of biologists, regardless of race, gender or socioeconomic status, in the field of developmental biology. DFB offers a week-long course consisting of active lectures, hands-on laboratory sessions, and professional development opportunities through interactions with scientists from a variety of backgrounds and careers. A major goal of DFB is to propel undergraduate students from underserved communities to pursue biomedical research opportunities and advanced degrees in science. To achieve this goal, we provide DFB participants with continuing access to a diverse network of scientists that students can utilize to secure opportunities and foster success throughout multiple stages of their research careers. Here, we describe the flourishing DFB program at the University of Michigan to encourage other institutions to create their own DFB programs.
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Biologia do Desenvolvimento , Estudantes , HumanosRESUMO
Hedgehog (HH) signaling is a major driver of tissue patterning during embryonic development through the regulation of a multitude of cell behaviors including cell fate specification, proliferation, migration, and survival. HH ligands signal through the canonical receptor PTCH1 and three co-receptors, GAS1, CDON and BOC. While previous studies demonstrated an overlapping and collective requirement for these co-receptors in early HH-dependent processes, the early embryonic lethality of Gas1;Cdon;Boc mutants precluded an assessment of their collective contribution to later HH-dependent signaling events. Specifically, a collective role for these co-receptors during limb development has yet to be explored. Here, we investigate the combined contribution of these co-receptors to digit specification, limb patterning and long bone growth through limb-specific conditional deletion of Cdon in a Gas1;Boc null background. Combined deletion of Gas1, Cdon and Boc in the limb results in digit loss as well as defects in limb outgrowth and long bone patterning. Taken together, these data demonstrate that GAS1, CDON and BOC are collectively required for HH-dependent patterning and growth of the developing limb.
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Moléculas de Adesão Celular , Proteínas Hedgehog , Receptores de Superfície Celular , Feminino , Gravidez , Proteínas de Transporte , Moléculas de Adesão Celular/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas Ligadas por GPI/metabolismo , Proteínas Hedgehog/metabolismo , Receptores de Superfície Celular/metabolismo , AnimaisRESUMO
Animal welfare and ethics are important factors influencing wildlife conservation practice, and critics are increasingly challenging the underlying ethics and motivations supporting common conservation practices. "Compassionate Conservationists" argue that all conservationists should respect the rights of individual sentient animals and approach conservation problems from a position of compassion, and that doing so requires implementing practices that avoid direct harm to individual animals. In this way Compassionate Conservationists seek to contrast themselves with "Traditional Conservationists" who often express consequentialist decision-making processes that ostensibly aim to dispassionately minimize net animal harms, resulting in the common use of practices that directly harm or kill some animals. Conservationists and other observers might therefore conclude that the two sides of this debate are distinct and/or that their policy proscriptions produce different welfare outcomes for animals. To explore the validity of this conclusion we review the ethical philosophies underpinning two types of Compassionate Conservation-deontology and virtue ethics. Deontology focusses on animal rights or the moral duties or obligations of conservationists, whereas virtue ethics focusses on acting in ways that are virtuous or compassionate. We demonstrate that both types permit the intentional harm and killing of animals when faced with common conservation problems where animals will be harmed no matter what the conservationist does or does not do. We then describe the applied decision-making processes exhibited by Compassionate Conservationists (of both types) and Traditional Conservationists to show that they may each lead to the implementation of similar conservation practices (including lethal control) and produce similar outcomes for animals, despite the perceived differences in their ethical motivations. The widespread presence of wildlife conservation problems that cannot be resolved without causing at least some harm to some animals means that conservationists of all persuasions must routinely make trade-offs between the welfare of some animals over others. Compassionate Conservationists do this from an explicit position of animal rights and/or compassion, whereas Traditional Conservationists respect animal rights and exhibit this same compassion implicitly. These observations lead to the conclusion that Compassionate Conservation is indistinguishable from traditional forms of conservation in practice, and that the apparent disagreement among conservationists primarily concerns the effectiveness of various wildlife management practices at minimizing animal harm, and not the underlying ethics, motivations or morality of those practices.
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Hedgehog signaling controls tissue patterning during embryonic and postnatal development and continues to play important roles throughout life. Characterizing the full complement of Hedgehog pathway components is essential to understanding its wide-ranging functions. Previous work has identified neuropilins, established semaphorin receptors, as positive regulators of Hedgehog signaling. Neuropilins require plexin co-receptors to mediate semaphorin signaling, but the role of plexins in Hedgehog signaling has not yet been explored. Here, we provide evidence that multiple plexins promote Hedgehog signaling in NIH/3T3 mouse fibroblasts and that plexin loss of function in these cells results in significantly reduced Hedgehog pathway activity. Catalytic activity of the plexin GTPase-activating protein (GAP) domain is required for Hedgehog signal promotion, and constitutive activation of the GAP domain further amplifies Hedgehog signaling. Additionally, we demonstrate that plexins promote Hedgehog signaling at the level of GLI transcription factors and that this promotion requires intact primary cilia. Finally, we find that plexin loss of function significantly reduces the response to Hedgehog pathway activation in the mouse dentate gyrus. Together, these data identify plexins as novel components of the Hedgehog pathway and provide insight into their mechanism of action.
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Proteínas Hedgehog , Semaforinas , Animais , Proteínas de Transporte , Moléculas de Adesão Celular , Proteínas Ativadoras de GTPase/metabolismo , Proteínas Hedgehog/metabolismo , Camundongos , Proteínas do Tecido Nervoso , Neuropilinas/metabolismo , Semaforinas/metabolismo , Fatores de Transcrição/metabolismoRESUMO
Proper Hedgehog (HH) signaling is essential for embryonic development, while aberrant HH signaling drives pediatric and adult cancers. HH signaling is frequently dysregulated in pancreatic cancer, yet its role remains controversial, with both tumor-promoting and tumor-restraining functions reported. Notably, the GLI family of HH transcription factors (GLI1, GLI2, GLI3), remain largely unexplored in pancreatic cancer. We therefore investigated the individual and combined contributions of GLI1-3 to pancreatic cancer progression. At pre-cancerous stages, fibroblast-specific Gli2/Gli3 deletion decreases immunosuppressive macrophage infiltration and promotes T cell infiltration. Strikingly, combined loss of Gli1/Gli2/Gli3 promotes macrophage infiltration, indicating that subtle changes in Gli expression differentially regulate immune infiltration. In invasive tumors, Gli2/Gli3 KO fibroblasts exclude immunosuppressive myeloid cells and suppress tumor growth by recruiting natural killer cells. Finally, we demonstrate that fibroblasts directly regulate macrophage and T cell migration through the expression of Gli-dependent cytokines. Thus, the coordinated activity of GLI1-3 directs the fibroinflammatory response throughout pancreatic cancer progression.
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Proteínas Hedgehog , Neoplasias Pancreáticas , Adulto , Criança , Feminino , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neoplasias Pancreáticas/genética , Gravidez , Proteína GLI1 em Dedos de Zinco/genética , Proteína Gli2 com Dedos de Zinco/genética , Proteína Gli3 com Dedos de Zinco/genéticaRESUMO
DNA-binding transcription factors (TFs) remain challenging to target with molecular probes. Many TFs function in part through interaction with Mediator, a 26-subunit complex that controls RNA polymerase II activity genome-wide. We sought to block p53 function by disrupting the p53-Mediator interaction. Through rational design and activity-based screening, we characterize a stapled peptide, with functional mimics of both p53 activation domains, that blocks p53-Mediator binding and selectively inhibits p53-dependent transcription in human cells; importantly, this "bivalent" peptide has negligible impact, genome-wide, on non-p53 target genes. Our proof-of-concept strategy circumvents the TF entirely and targets the TF-Mediator interface instead, with desired functional outcomes (i.e., selective inhibition of p53 activation). Furthermore, these results demonstrate that TF activation domains represent viable starting points for Mediator-targeting molecular probes, as an alternative to large compound libraries. Different TFs bind Mediator through different subunits, suggesting this strategy could be broadly applied to selectively alter gene expression programs.
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Fatores de Transcrição , Proteína Supressora de Tumor p53 , Humanos , Sondas Moleculares , Peptídeos/metabolismo , Ligação Proteica , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
BACKGROUND AND AIMS: In extrahepatic bile duct (EHBD) cholangiopathies, including primary sclerosing cholangitis, a reactive cholangiocyte phenotype is associated with inflammation and epithelial hyperproliferation. The signaling pathways involved in EHBD injury response are poorly understood. In this study, we investigated the role of Hedgehog (HH) signaling and its downstream effectors in controlling biliary proliferation and inflammation after EHBD injury. APPROACH AND RESULTS: Using mouse bile duct ligation as an acute EHBD injury model, we used inhibitory paradigms to uncover mechanisms promoting the proliferative response. HH signaling was inhibited genetically in Gli1-/- mice or by treating wild-type mice with LDE225. The role of neutrophils was tested using chemical (SB225002) and biological (lymphocyte antigen 6 complex locus G6D [Ly6G] antibodies) inhibitors of neutrophil recruitment. The cellular response was defined through morphometric quantification of proliferating cells and CD45+ and Ly6G+ immune cell populations. Key signaling component expression was measured and localized to specific EHBD cellular compartments by in situ hybridization, reporter strain analysis, and immunohistochemistry. Epithelial cell proliferation peaked 24 h after EHBD injury, preceded stromal cell proliferation, and was associated with neutrophil influx. Indian HH ligand expression in the biliary epithelium rapidly increased after injury. HH-responding cells and neutrophil chemoattractant C-X-C motif chemokine ligand 1 (CXCL1) expression mapped to EHBD stromal cells. Inhibition of HH signaling blocked CXCL1 induction, diminishing neutrophil recruitment and the biliary proliferative response to injury. Directly targeting neutrophils by inhibition of the CXCL1/C-X-C motif chemokine receptor 2/Ly6G signaling axis also decreased biliary proliferation. CONCLUSIONS: HH-regulated CXCL1 orchestrates the early inflammatory response and biliary proliferation after EHBD injury through complex cellular crosstalk.
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Ductos Biliares Extra-Hepáticos , Quimiocina CXCL1 , Proteínas Hedgehog , Animais , Ductos Biliares Extra-Hepáticos/metabolismo , Proteínas Hedgehog/metabolismo , Inflamação , Ligantes , Camundongos , Receptores de Quimiocinas , Proteína GLI1 em Dedos de ZincoRESUMO
BACKGROUND & AIMS: Oncogenic Kirsten Rat Sarcoma virus (KRAS) is the hallmark mutation of human pancreatic cancer and a driver of tumorigenesis in genetically engineered mouse models of the disease. Although the tumor cell-intrinsic effects of oncogenic Kras expression have been widely studied, its role in regulating the extensive pancreatic tumor microenvironment is less understood. METHODS: Using a genetically engineered mouse model of inducible and reversible oncogenic Kras expression and a combination of approaches that include mass cytometry and single-cell RNA sequencing we studied the effect of oncogenic KRAS in the tumor microenvironment. RESULTS: We have discovered that non-cell autonomous (ie, extrinsic) oncogenic KRAS signaling reprograms pancreatic fibroblasts, activating an inflammatory gene expression program. As a result, fibroblasts become a hub of extracellular signaling, and the main source of cytokines mediating the polarization of protumorigenic macrophages while also preventing tissue repair. CONCLUSIONS: Our study provides fundamental knowledge on the mechanisms underlying the formation of the fibroinflammatory stroma in pancreatic cancer and highlights stromal pathways with the potential to be exploited therapeutically.
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Neoplasias Pancreáticas , Proteínas Proto-Oncogênicas p21(ras) , Animais , Fibroblastos/metabolismo , Vírus do Sarcoma Murino de Kirsten/metabolismo , Camundongos , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Microambiente Tumoral , Neoplasias PancreáticasRESUMO
Climate change has started impacting species, ecosystems, genetic diversity within species, and ecological interactions and is thus a serious threat to conserving biodiversity globally. In the absence of adequate adaptation measures, biodiversity may continue to decline, and many species will possibly become extinct. Given that global temperature continues to increase, climate change adaptation has emerged as an overarching framework for conservation planning. We identified both ongoing and probable climate change adaptation actions for greater one-horned rhinoceros conservation in Nepal through a combination of literature review, key informant surveys (n = 53), focus group discussions (n = 37) and expert consultation (n = 9), and prioritised the identified adaptation actions through stakeholder consultation (n = 17). The majority of key informants (>80%) reported that climate change has been impacting rhinoceros, and more than 65% of them believe that rhinoceros habitat suitability in Nepal has been shifting westwards. Despite these perceived risks, climate change impacts have not been incorporated well into formal conservation planning for rhinoceros. Out of 20 identified adaptation actions under nine adaptation strategies, identifying and protecting climate refugia, restoring the existing habitats through wetland and grassland management, creating artificial highlands in floodplains to provide rhinoceros with refuge during severe floods, and translocating them to other suitable habitats received higher priority. These adaptation actions may contribute to reducing the vulnerability of rhinoceros to the likely impacts of climate change. This study is the first of its kind in Nepal and is expected to provide a guideline to align ongoing conservation measures into climate change adaptation planning for rhinoceros. Further, we emphasise the need to integrating likely climate change impacts while planning for rhinoceros conservation and initiating experimental research and monitoring programs to better inform adaptation planning in the future.
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Biodiversidade , Ecossistema , Animais , Conservação dos Recursos Naturais , Mudança Climática , Nepal , Temperatura , PerissodáctilosRESUMO
BACKGROUND: Hedgehog (HH) signaling is essential for homeostasis in gustatory fungiform papillae (FP) and taste buds. However, activities of HH antagonists in these tissues remain unexplored. We investigated a potential role for HH-interacting protein (HHIP), an endogenous pathway antagonist, in regulating HH signaling during taste organ homeostasis. We found a restricted pattern of Hhip-expressing cells in the anterior epithelium of each nongustatory filiform papilla (FILIF) only. To test for roles in antagonism of HH signaling, we investigated HHIP after pathway inhibition with SMO inhibition via sonidegib and Smo deletion, Gli2 deletion/suppression, or with chorda tympani/lingual nerve cut. RESULTS: In all approaches, the HHIP expression pattern was retained in FILIF suggesting HH-independent regulation of HHIP. Remarkably, after pathway inhibition, HHIP expression was detected also in the conical, FILIF-like atypical FP. We found a close association of de novo expression of HHIP in atypical FP with loss of Gli1+, HH-responding cells. Further, we report that PTCH1 is another potential HH antagonist in FILIF that co-localizes with HHIP. CONCLUSIONS: After HH pathway inhibition the ectopic expression of HHIP correlates with a FILIF-like morphology in atypical FP and we propose that localized expression of the HH antagonist HHIP regulates pathway inhibition to maintain FILIF during tongue homeostasis.
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Papilas Gustativas , Expressão Ectópica do Gene , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Homeostase , Papilas Gustativas/metabolismo , LínguaRESUMO
Growth arrest-specific 1 (GAS1) acts as a co-receptor to patched 1, promoting sonic hedgehog (SHH) signaling in the developing nervous system. GAS1 mutations in humans and animal models result in forebrain and craniofacial malformations, defects ascribed to a function for GAS1 in SHH signaling during early neurulation. Here, we confirm loss of SHH activity in the forebrain neuroepithelium in GAS1-deficient mice and in induced pluripotent stem cell-derived cell models of human neuroepithelial differentiation. However, our studies document that this defect can be attributed, at least in part, to a novel role for GAS1 in facilitating NOTCH signaling, which is essential to sustain a persistent SHH activity domain in the forebrain neuroepithelium. GAS1 directly binds NOTCH1, enhancing ligand-induced processing of the NOTCH1 intracellular domain, which drives NOTCH pathway activity in the developing forebrain. Our findings identify a unique role for GAS1 in integrating NOTCH and SHH signal reception in neuroepithelial cells, and they suggest that loss of GAS1-dependent NOTCH1 activation contributes to forebrain malformations in individuals carrying GAS1 mutations.
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Proteínas de Ciclo Celular/metabolismo , Proteínas Hedgehog/metabolismo , Prosencéfalo/metabolismo , Receptor Notch1/metabolismo , Animais , Proteínas de Ciclo Celular/deficiência , Diferenciação Celular , Embrião de Mamíferos , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Epitélio/metabolismo , Proteínas Ligadas por GPI/deficiência , Proteínas Ligadas por GPI/metabolismo , Humanos , Camundongos , Mutação , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Receptor Patched-1/metabolismo , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Prosencéfalo/citologia , Prosencéfalo/embriologia , Transdução de SinaisRESUMO
Removal or loss of top-predators has been predicted to cause cascading negative effects for ecosystems, including mesopredator release. However, reliable evidence for these processes in terrestrial systems has been mixed and equivocal due, in large part, to the systemic and continued use of low-inference study designs to investigate this issue. Even previous large-scale manipulative experiments of strong inferential value have been limited by experimental design features (i.e. failure to prevent migration between treatments) that constrain possible inferences about the presence or absence of mesopredator release effects. Here, we build on these previous strong-inference experiments and report the outcomes of additional large-scale manipulative experiments to eradicate Australian dingoes from two fenced areas where dingo migration was restricted and where theory would predict an increase in extant European red foxes, feral cats and goannas. We demonstrate the removal and suppression of dingoes to undetectable levels over 4-5 years with no corresponding increases in mesopredator relative abundances, which remained low and stable throughout the experiment at both sites. We further demonstrate widespread absence of negative relationships between predators, indicating that the mechanism underpinning predicted mesopredator releases was not present. Our results are consistent with all previous large-scale manipulative experiments and long-term mensurative studies which collectively demonstrate that (1) dingoes do not suppress red foxes, feral cats or goannas at the population level, (2) repeated, temporary suppression of dingoes in open systems does not create mesopredator release effects, and (3) removal and sustained suppression of dingoes to undetectable levels in closed systems does not create mesopredator release effects either. Our experiments add to similar reports from North America, Asia, Europe and southern Africa which indicate that not only is there a widespread absence of reliable evidence for these processes, but there is also a large and continually growing body of experimental evidence of absence for these processes in many terrestrial systems. We conclude that although sympatric predators may interact negatively with each other on smaller spatiotemporal scales, that these negative interactions do not always scale-up to the population level, nor are they always strong enough to create mesopredator suppression or release effects.
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Ethical food choices have become an important societal theme in post-industrial countries. Many consumers are particularly interested in the animal welfare implications of the various foods they may choose to consume. However, concepts in animal welfare are rapidly evolving towards consideration of all animals (including wildlife) in contemporary approaches such as "One Welfare". This approach requires recognition that negative impacts (harms) may be intentional and obvious (e.g., slaughter of livestock) but also include the under-appreciated indirect or unintentional harms that often impact wildlife (e.g., land clearing). This is especially true in the Anthropocene, where impacts on non-human life are almost ubiquitous across all human activities. We applied the "harms" model of animal welfare assessment to several common food production systems and provide a framework for assessing the breadth (not intensity) of harms imposed. We considered all harms caused to wild as well as domestic animals, both direct effects and indirect effects. We described 21 forms of harm and considered how they applied to 16 forms of food production. Our analysis suggests that all food production systems harm animals to some degree and that the majority of these harms affect wildlife, not livestock. We conclude that the food production systems likely to impose the greatest overall breadth of harms to animals are intensive animal agriculture industries (e.g., dairy) that rely on a secondary food production system (e.g., cropping), while harvesting of locally available wild plants, mushrooms or seaweed is likely to impose the least harms. We present this conceptual analysis as a resource for those who want to begin considering the complex animal welfare trade-offs involved in their food choices.